Volume 1 - Number 1 May - September 1997

Volume 24 - Number 11 November 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to , cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It is made for and by: clinicians and researchers in cytogenetics, molecular biology, oncology, haematology, and pathology. One main scope of the Atlas is to conjugate the scientific information provided by cytogenetics/molecular genetics to the clinical setting (diagnostics, prognostics and therapeutic design), another is to provide an encyclopedic knowledge in cancer genetics. The Atlas deals with cancer research and genomics. It is at the crossroads of research, virtual medical university (university and post-university e-learning), and telemedicine. It contributes to "meta-medicine", this mediation, using information technology, between the increasing amount of knowledge and the individual, having to use the information. Towards a personalized medicine of cancer.

It presents structured review articles ("cards") on: 1- Genes, 2- Leukemias, 3- Solid tumors, 4- Cancer-prone diseases, and also 5- "Deep insights": more traditional review articles on the above subjects and on surrounding topics. It also present 6- Case reports in hematology and 7- Educational items in the various related topics for students in Medicine and in Sciences. The Atlas of Genetics and Cytogenetics in Oncology and Haematology does not publish research articles.

See also: http://documents.irevues.inist.fr/bitstream/handle/2042/56067/Scope.pdf

Editorial correspondance

Jean-Loup Huret, MD, PhD, [email protected]

Editor, Editorial Board and Publisher See:http://documents.irevues.inist.fr/bitstream/handle/2042/48485/Editor-editorial-board-and-publisher.pdf

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008. The Atlas is hosted by INIST-CNRS (http://www.inist.fr) Staff: Vanessa Le Berre Philippe Dessen is the Database Directorof the on-line version (Gustave Roussy Institute – Villejuif – France).

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Editors-in-Chief Jesús María Hernández Rivas (Salamanca, Spain) Paola Dal Cin (Boston, Massachusetts) Jean-Loup Huret (Poitiers, France) Hematology Section Editor Ana E. Rodríguez, Teresa Gonzalez (Salamanca, Spain) Bone Tumors Section Editor Judith Bovee (Leiden, Netherlands) Head and Neck Tumors Section Editor Cécile Badoual (Paris, France) Urinary Tumors Section Editor Paola Dal Cin (Boston, Massachusetts) Pediatric Tumors Section Editor Frederic G. Barr (Bethesda, Maryland) Cancer Prone Diseases Section Editor Gaia Roversi (Milano, Italy) Cell Cycle Section Editor João Agostinho Machado-Neto (São Paulo, Brazil) DNA Repair Section Editor Godefridus Peters (Amsterdam, Netherlands) Epigenetics Section Editor Roberto Piergentili (Rome, Italy) Hematopoeisis Section Editor Olga Weinberg (Boston, Massachusetts) Hormones and Growth factors Section Editor Gajanan V. Sherbet (Newcastle upon Tyne, UK) Mitosis Section Editor Patrizia Lavia (Rome, Italy) Oxidative stress Section Editor Thierry Soussi (Stockholm, Sweden/Paris, France) WNT pathway Section Editor Alessandro Beghini (Milano, Italy) B-cell activation Section Editors Anette Gjörloff Wingren, Barnabas Nyesiga (Malmö, Sweden) Board Members Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Alessandro Beghini Department of Health Sciences, University of Milan, Italy; [email protected] Judith Bovée 2300 RC Leiden, The Netherlands; [email protected] Antonio Cuneo Dipartimento di ScienzeMediche, Sezione di Ematologia e Reumatologia Via Aldo Moro 8, 44124 - Ferrara, Italy; [email protected] Paola Dal Cin Department of Pathology, Brigham, Women's Hospital, 75 Francis Street, Boston, MA 02115, USA; [email protected] IRBA, Departement Effets Biologiques des Rayonnements, Laboratoire de Dosimetrie Biologique des Irradiations, Dewoitine C212, 91223 François Desangles Bretigny-sur-Orge, France; [email protected] Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, Roosevelt Dr. Oxford, OX37BN, UK Enric Domingo [email protected] Ayse Elif Erson- Department of Biological Sciences, Middle East Technical University, Ankara, Turkey; [email protected] Bensan Ad Geurts van Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, 6500 HB Nijmegen, Kessel The Netherlands; [email protected] Department of Pediatrics and Adolescent Medicine, St. Anna Children's Hospital, Medical University Vienna, Children's Cancer Research Oskar A. Haas Institute Vienna, Vienna, Austria. [email protected] Anne Hagemeijer Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium; [email protected] Department of Pathology, The Ohio State University, 129 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA; Nyla Heerema [email protected] Sakari Knuutila Hartmann Institute and HUSLab, University of Helsinki, Department of Pathology, Helsinki, Finland; [email protected] Lidia Larizza Lab Centro di Ricerche e TecnologieBiomedicheIRCCS-IstitutoAuxologico Italiano Milano, Italy; l.larizza@auxologico Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Roderick Mc Leod Germany; [email protected] Cristina Mecucci Hematology University of Perugia, University Hospital S.Mariadella Misericordia, Perugia, Italy; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Fredrik Mertens [email protected] Konstantin Miller Institute of Human Genetics, Hannover Medical School, 30623 Hannover, Germany; [email protected] Department of Clinical Genetics, University and Regional Laboratories, Lund University, SE-221 85 Lund, Sweden; Felix Mitelman [email protected] Hossain Mossafa Laboratoire CERBA, 95066 Cergy-Pontoise cedex 9, France; [email protected] Department of Human, Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms, Cell Cultures, Braunschweig, Stefan Nagel Germany; [email protected] Florence Pedeutour Laboratory of Solid Tumors Genetics, Nice University Hospital, CNRSUMR 7284/INSERMU1081, France; [email protected] Department of Pathology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Mail Stop 250, Memphis, Tennessee 38105- Susana Raimondi 3678, USA; [email protected] Clelia Tiziana Department of Biology, University of Bari, Bari, Italy; [email protected] Storlazzi Sabine Strehl CCRI, Children's Cancer Research Institute, St. Anna Kinderkrebsforschunge.V., Vienna, Austria; [email protected] Nancy Uhrhammer Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, Clermont-Ferrand, France; [email protected] Dan L. Van Dyke Mayo Clinic Cytogenetics Laboratory, 200 First St SW, Rochester MN 55905, USA; [email protected] Roberta Vanni Universita di Cagliari, Dipartimento di ScienzeBiomediche(DiSB), CittadellaUniversitaria, 09042 Monserrato (CA) - Italy; [email protected]

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Volume 24, Number 11, November 2020

Table of contents

Gene Section

EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) 387 Luigi Cristiano RARA (Retinoic acid , alpha) 396 Franck Viguié TNIK (TRAF2 and NCK interacting kinase) 408 Adriana Cassaro TPH1 (tryptophan hydroxylase 1) 414 Rafig Gurbanov, Sevinç Karaçam XIAP (X-linked inhibitor of apoptosis) 424 Catarina Sofia Reis Silva, Gabriel Henrique Barbosa, Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Luigi Cristiano Aesthetic and medical biotechnologies research unit, Prestige, Terranuova Bracciolini, Italy; [email protected] - [email protected]

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/EEF1E1ID40409ch6p24.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70858/03-2020-EEF1E1ID40409ch6p24.pdf DOI: 10.4267/2042/70858

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Keywords EEF1E1; eukaryotic translation elongation factor 1 Eukaryotic translation elongation factor 1 epsilon 1, epsilon 1; AIMP3; p18; Translation; Translation alias EEF1E1, is a -coding gene that plays a elongation factor; protein synthesis; cancer; role in the elongation step of translation. In oncogene; cancer marker particular, it is an auxiliary component of the macromolecular aminoacyl-tRNA synthase complex (MARS). Identity Its expression is found frequently altered in human Other names: P18, AIMP3, ARS-interacting cancer cells and it is considered a putative tumor multifunctional protein 3, Multisynthase Complex suppressor gene. Auxiliary Component P18, Elongation Factor P18 This review collects the data on DNA/RNA, the HGNC (Hugo): EEF1E1 protein encoded and the diseases where EEF1E1 is involved. Location: 6p24.3

Figure. 1. EEF1E1 gene and splicing variants/isoforms. The figure shows the on 6 of the EEF1E1 gene (reworked from https://www.ncbi.nlm.nih.gov/gene; http://grch37.ensembl.org; www.genecards.org)

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 387 EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1) Cristiano L

Two main alternative splicing transcript variants for DNA/RNA EEF1E1 were detected although several others were reported. Description In addition, it was speculated the presence of six EEF1E1 (eukaryotic translation elongation factor 1 protein isoforms, but only two are properly epsilon 1) was identified for the first time by Mao described, i.e. the isoform 1 of 174 residues and the and colleagues in 1998 (Mao et al, 1998). EEF1E1 is isoform 2 that counts 139 residues. a protein-coding gene that starts at 8,079,395 nt and The main characteristics of the alternative splicing ends at 8,102,595 nt from pter. It has a length of transcript variants are reported in Table.1. 23,201 bp, counts 5 exons, and the current reference The transcript variant 1 mRNA has reference sequence is NC_000006.12. sequence NM_004280.5 and it is 1047 bp long. The It is proximal to BLOC1S5 (biogenesis of lysosomal 5'UTR counts 27 nt, the CDS is extended from 28 to organelles complex 1 subunit 5, alias MUTED) 552 nt, while the 3'UTR covers the last 495 nt. gene. Read-through transcription exists between The transcript variant 2 mRNA has reference BLOC1S5 gene and EEF1E1 gene with forming the sequence NM_001135650.2 and it is 562 bp long. read-through transcript EEF1E1-BLOC1S5 (alias The 5'UTR counts 27 nt, the CDS is extended from EEF1E1-MUTED) that is a candidate for nonsense- 28 to 447 nt, while the 3'UTR covers the last 115 nt. mediated mRNA decay (NMD) and it is unlikely to Pseudogene produce a protein product (He et al, 2018). Near to the genomic sequence of EEF1E1 there is a According to Gene, the analysis of the human strong promoter transcriptional element that is genome revealed the presence of an EEF1E1-related located at +1.0 kb. Enhancer transcriptional elements pseudogene on . This pseudogene was are located at +22.0 Kb and at +18.1 Kb respectively. appointed as eukaryotic translation elongation factor 1 epsilon 1 pseudogene 1, alias EEF1E1P1 and it is Transcription classified as a processed pseudogene Alternative splicing for EEF1E1 brings to multiple (http://www.ensembl.org/index.html). Its gene ID is transcript variants. In addition, a read-through 100130388, its reference is NC_000002.12, and its transcription is known between EEF1E1 and the location is 2q13. EEF1E1P1 starts at 111,887,890 nt neighboring downstream MUTED (muted homolog) and ends at 111,889,485 nt with a length of 1,596 nt. gene. MW Varian Exon Lengh Isofor Lengh Name RefSeq (1) Transcript ID Type Alias RefSeq (2) (kDa pI t s t (bp) m t (aa) ) protei EEF1E1 ENST00000488226. n - - 2 443 - - - 94 (?) (?) -001 2 codin g protei EEF1E1 ENST00000379715. n isoform O43324 19.8 8.5 Var.1 NM_004280.5 4 1077 NP_004271.1 174 -002 5 codin 1 -1 1 5 g protei EEF1E1 ENST00000507463. n 16.6 - - 3 654 - - - 150 (?) -003 1 codin 9 g protei EEF1E1 NM_001135650 ENST00000429723. n isoform O43324 NP_001129122 15.5 7.9 Var.2 4 562 139 -004 .2 2 codin 2 -2 .1 5 5 g protei EEF1E1 ENST00000502429. n - - 4 591 - - - 136 (?) (?) -005 1 codin g protei EEF1E1 ENST00000515633. n - - 3 460 - - - 56 5.89 (?) -006 1 codin g

Table.1 Alterative splicing variants and isoforms of EEF1E1. (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; https://web.expasy.org/protparam/; https://www.uniprot.org). ncRNA = non-coding RNA; nonsense md = nonsense mediated decay; (?) = undetermined; MW = molecular weight; pI = theoretical pI.

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Figure.2 eEF1E1 protein. Graphical representation of eEF1E1 protein isoforms with the evidence of the main verified post- translational modifications (reworked from http://grch37.ensembl.org; https://www.ncbi.nlm.nih.gov; http://bioinf.umbc.edu/dmdm/gene_prot_page.php).

It virtually encodes a non-coding transcript of 430 bp characterized followed by a linker domain, while the named EEF1E1P1-201 (Ensembl Ref: major differences between the two isoforms are in ENST00000446998.2). The real presence of this the carboxyl half terminal. In fact, in the carboxyl transcript and its possible role in the cell are totally half terminal of isoform 1 there are reported two unknown. domain overlapping, i.e. a S-transferase If EEF1E1P1 has any regulatory role in the C-terminal-like domain (GST_C_AIMP3), folded in expression of the respective gene as described for alpha-helical, and a more general and not well others (Hirotsune et al., 2003), is only speculation in characterized C-terminal domain. the absence of experimental evidence. Currently, In isoform 2, there is a unique region called C- there is no evidence about the involvement of this terminal domain of the Glutathione S-transferase pseudogene in human cancers or in other diseases. family (GST_C_family). The fold of this domain is alpha-helical (see figure.2). Protein EEF1E1 interacts with other members of the MARS complex and one interactional model was proposed Description (Mirande, 2017) although its exact interactions need The eukaryotic translation elongation factor 1 to be still clarified. epsilon 1 (alias eEF1E1, p18, AIMP3) is the smallest Post-translational modifications. Some post- component of the Multiaminoacyl-tRNA Synthetase translational modifications are observed, such as complex (alias MARS). The exact position of phosphorylation and acetylation EEF1E1 in the MARS complex is still unknown. (https://www.ncbi.nlm.nih.gov). However, it seems to be localized on the surface of the MARS complex and it seems to interact with the Expression eEF1H complex (Deineko V.V., 2008). eEF1E1 is expressed widely in human tissues and EEF1E1 is a small globular protein with a length of normal cells (https://www.genecards.org; 174 amino acids and a molecular weight of 19,8 kDa. https://www.proteinatlas.org/ENSG00000124802- eEF1E1 shows strong sequence similarity with EEF1E1/tissue) while its expression is altered in eukaryotic translation elongation factor 1 beta 2 ( many cancer types. Frequently it is downregulated in EEF1B2) and eukaryotic translation elongation various cancer tissues (Park et al, 2005). factor 1 gamma ( EEF1G) (Quevillon and Mirande, Cells that show overexpression of eEF1E1 show an 1996) and with the N-terminal sequence of valyl- acceleration of senescence and also defects in tRNA synthetase (Deineko V.V., 2008). nuclear morphology (Oh et al, 2010). eEF1E1 shows many domains in both isoforms: the amino half terminal is unique for both isoforms and Localisation shows an N-terminal-like domain not well EEF1E1 is located mostly in the cytoplasm but it was also found in the nucleus.

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Figure 3. Cellular localization of eEF1E1(p18). In the figure is reported the cellular localization of eEF1E1 obtaining by immunofluorescent staining (antibody HPA027901). In particular, eEF1E1 shows to be localized both in cytosol and nucleoplasm in (1) A-431 cell line and (2) U-2 OS cell line. In green: antiboy for eEF1E1; In red: microtubules (reworked from https://www.proteinatlas.org/ ENSG00000124802-EEF1E1/cell)

Function Other functions (non-canonical roles): in addition to what has already been said, it seems to play a role in It is well known that in eukaryotic cells the various embryonic development of the mammalian face components of translation machinery are properly and other structures (Fowles et al, 2003). organized into two main multienzyme structures: eEF1E1 has the ability to translocate into the nucleus eEF1H (macromolecular eukaryotic translation in response to DNA damage where it has a role in elongation factor-1 complex), formed by the the DNA damage response in association with translation elongation factors (EEF1B2, EEF1D, /threonine kinases ATM / ATR and TP53. In EEF1G) and VARS (valyl-tRNA synthetase), and fact, it was found a positive relationship between MARS (Multiaminoacyl-tRNA Synthetase complex expression levels of eEF1E1 and TP53, i.e. high or multi-tRNA synthetase complex, alias MSC), expression levels of eEF1E1 are correlated with formed by nine aminoacyl-tRNA synthetases elevated TP53 levels, while eEF1E1 depletion leads (AARSs) specific for amino acids Glu, Pro (EPRS1 to the block of TP53 induction (Park et al, 2005). The (glutaminylprolyl-tRNA synthetase)), Ile (IARS1), eEF1E1 loss-of-function phenotype leads to various Leu (LARS1), Met (MARS1, methionyl- kinds of abnormalities: in particular, one allele tRNAsynthetase), Gln (QARS1), Lys (KARS1), Arg inactivation increases the susceptibility to (RARS1), and Asp (DARS1) and other auxiliary spontaneous tumors while the inactivation of both non-synthetase protein components, called also EEF1E1 alleles caused embryonic lethality (Park et aminoacyl-tRNA synthetase (ARS)-interacting al, 2005). The importance of eEF1E1 in multifunctional (AIMPs), i.e AIMP1 (p43), embryogenesis is previously reported (Fowles et al, AIMP2 (p38) and eEF1E1 (AIMP3, alias p18)( Cho 2003) while in the context of the tumors, eEF1E1 et al, 2015; Shalak et al, 2007; Quevillon and could be a haploinsufficient tumor suppressor (Park Mirande, 1996). et al, 2005) that can accelerate cellular senescence It is well known that in eukaryotic cells the various (Kang et al, 2012). components of translation machinery Therefore, the eEF1E1 in involved in the degradation of mature main canonical function of eEF1E1 is to play a role Lamin A ( LMNA) which is a major component of as an auxiliary component of the macromolecular the nuclear envelope matrix (Tao et al, 2017). aminoacyl-tRNA synthetases complex in the elongation step of translation, in particular, it Homology interacts with several aminoacyl-tRNA synthetases (Tao et al, 2017) and it could contribute to the eEF1E1 is highly conserved and its homology anchorage of MARS complex to EF1H complex between the species is reported in Table.2 (Quevillon and Mirande, 1996).

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Circos plot for fusion events involving eEF1E1. The picture summarizes all fusion events concerning eEF1E1 and its fusion partners (from https://fusionhub.persistent.co.in/search_genewise.html).

DNA PROT repercussions on cellular behavior and so the Organism Species Symbol Identity Identity implications in cancer of these alterations. (%) (%) Human H.sapiens EEF1E1 100 100 Implicated in Chimpanzee P.troglodytes EEF1E1 99.2 100 Top note Macaco M.mulatta EEF1E1 97.5 99.4 A different expression level of EEF1E1 was Wolf C.lupus EEF1E1 92.5 96.0 observed in many cancer types compared to Cattle B.taurus EEF1E1 89.8 96.5 noncancerous control tissue. It is considered as a Mouse M.musculus Eef1e1 86.6 88.5 putative tumor suppressor, in particular for its Rat R.norvegicus Eef1e1 83.7 87.9 downregulation in gastric and colorectal cancers (Kim et al, 2011). In fact, high EEF1E1 expression Chicken G.gallus EEF1E1 75.9 77.6 seems to be related to better survival in these two Xenopus X.tropicalis Eef1e1 67.6 69.6 tumor types (Hassan et al, 2018). tropicalis However, Hassan et colleagues reported that Zebrafish D.rerio Eef1e1 63.0 63.7 EEF1E1 is overexpressed in many other cancer types Table.2 EEF1E1 homology (reworked from such as breast, lung, gastric, prostate, colorectal and ps://www.ncbi.nlm.nih.gov/homologene) liver tumors and this fact could predict poor survival (breast, lung, liver)(Hassan et al, 2018). Mutations Interesting is the role of inorganic arsenic (iAs) in A great number of mutations in the genomic the epigenetic alteration of DNA methylation in sequence and in the amino acid sequence for arsenic-induced diseases such as cancer of the EEF1E1 were discovered in cancer cells that are bladder, kidney, lung, liver, and prostate. It was obviously genetically more unstable respect normal revealed that EEF1E1 is one of many genes silenced ones. However, depletion of EEF1E1 causes itself and involved in iAs related-hypermethylation in an genomic instability in cells (Kim et al, 2018) and arsenic-methylated tumor suppressorome (Smeester makes the cells susceptible to transformation by et al, 2011). single oncogenes (Park et al, 2006). In addition, eEF1E1 is involved in some genomic The genomic alterations observed include also the translocations with the creation of numerous fusion formation of novel fusion genes. However, there are genes (Table.3). no sufficient experimental data yet to understand the

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Name 5' end 3' end Loc1 Loc2 Description Type Disease Organ Code Ref. CDYL/EEF1E1 CDYL EEF1E1 6p25 6p24.3 t(6;6)(p25;p24) Translocation Malignant melanoma Skin SKCM 1 EEF1E1/AEBP2 EEF1E1 AEBP2 6p24.3 12p12.3 t(6;12)(p24;p12) Translocation - - - - Readthrough EEF1E1-BLOC1S5 EEF1E1 BLOC1S5 6p24.3 6p24.3 Fusion gene - - - - transcription EEF1E1/CD2AP EEF1E1 CD2AP 6p24.3 6p12.3 t(6;6)(p24;p12) Translocation - - - - EEF1E1/DSC2 EEF1E1 DSC2 6p24.3 18q12.1 t(6;18)(p24;q12) Translocation - - - - EEF1E1/EYS EEF1E1 EYS 6p24.3 6q12 t(6;6)(p24;q12) Translocation Adenocarcinoma Breast BRCA 2 EEF1E1/KRTDAP EEF1E1 KRTDAP 6p24.3 19q13.12 t(6;19)(p24;q13) Translocation - - - - EEF1E1/NSMCE4A EEF1E1 NSMCE4A 6p24.3 10q26.13 t(6;10)(p24;q26) Translocation - - - - EEF1E1/RAB23 EEF1E1 RAB23 6p24.3 6p12.1 t(6;12)(p24;p12) Translocation - - - - EEF1E1/RREB1 EEF1E1 RREB1 6p24.3 6p24.3 t(6;6)(p24;p24) Fusion gene - - - - Mesenchymal tumor, INPP4A/EEF1E1 INPP4A EEF1E1 2q11 6p24.3 t(2;6)(q11;p24) Translocation - - 1 NOS PSMG4/EEF1E1 PSMG4 EEF1E1 6p25 6p24.3 t(6;6)(p25;p24) Translocation Adenocarcinoma Breast BRCA 1 Central Astrocytoma, grade RREB1/EEF1E1 RREB1 EEF1E1 6p24.3 6p24.3 t(6;6)(p24;p24) Fusion gene Nervous GBM 2,3 III-IV/Glioblastoma System TG/EEF1E1 TG EEF1E1 8q24.22 6p24.3 t(6;8)(p24;q24) Translocation - - - - Table.3 EEF1E1 rearrangements: translocations and fusion genes (reworked from: http://www.tumorfusions.org; https://mitelmandatabase.isb-cgc.org/; http://quiver.archerdx.com; http://atlasgeneticsoncology.org//Bands/6p24.html#REFERENCES; [ (?) ] unknown; [ 1 ] Hu et al, 2018; [ 2 ] Yoshihara et al, 2015; [ 3 ] Gao et al 2018; [ - ] no reference

Ankylosing spondylitis Brain and central nervous system It is found that the expression levels of EEF1E1 are (CNS) cancers significantly upregulated in whole blood of EEF1E1 is upregulated in astrocytoma and ankylosing spondylitis (AS) patients respect control oligodendroglioma while for glioblastoma and group and these findings could be attributed to glioma no significant difference in expression levels genetic mutations on EEF1E1 gene. This may have was observed. High levels of EEF1E1 could be an important significance in the pathogenesis of AS predicted better survival outcomes (Hassan et al, because eEF1E1 may be involved in AS related- 2018). In addition, one genomic alteration was inflammation by upregulating TP53 and pro- observed both in astrocytoma and glioblastoma, i.e. inflammatory cytokines. This may suggest the use of the fusion gene t(6;6)(p24;p24) RREB1 /EEF1E1 EEF1E1 as an underlying genetic biomarker for the (Gao et al, 2018; Yoshihara et al, 2015). There are diagnosis of AS but other research are needed to no data about the respective chimeric transcript or determine the exact role of eEF1E1 overexpression protein and so this genomic alteration is still poorly in AS (Fan et al, 2019) understood. Autism spectrum disorders Breast cancer EEF1E1 appears in research on developmental delay and autism spectrum disorders focused on deletions Currently, for EEF1E1 there is no significant in chromosome 6p22.3-p24.3 (Celestino-Soper et al, difference in expression, between breast cancer and 2012). However, is still not clear its role in these normal breast tissues (Hassan et al, 2018; Guglielmi diseases. et al, 2013). The prognostic significance for EEF1E1 is that a higher expression level has a significant Bladder cancers correlation with relapse-free survival (RFS) and In general, eEF1E1 is found to be down-regulated in distant metastasis-free survival (DMFS) but not with bladder cancers. eEF1E1 is expressed at moderate either overall survival (OS) or post-progression and high levels in all normal urothelium tissues survival (PPS) while high expression levels of while only a part of bladder cancers shows this EEF1E1 are strongly associated with poor RFS in the expression's pattern. The loss of eEF1E1 expression luminal A and B subtypes (Hassan et al, 2018). is more evident in late-stage (≥ T2) bladder tumours Other authors reported that EEF1E1 is down- and can be associated with survival in muscle- regulated in breast cancer and linked to the genomic invasive bladder cancers (MIBC) patients following instability of these cells (Iofrida et al, 2012). In radiotherapy (Gurung et al, 2015). addition, some genomic alteration was observed in breast adenocarcinoma such as the translocation

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t(6;6)(p24;q12) EEF1E1/ EYS and t(6;6)(p25;p24) between the expression levels of highly up-regulated PSMG4 /EEF1E1 (Hu et al., 2018). There are no data in liver cancer (HULC) long non-coding RNA and about the respective chimeric transcripts or proteins eEF1E1 in HCC. In fact, if HULC is over-expressed and so these genomic alterations are still poorly the expression levels of eEF1E1 fall down and on the understood. contrary if expression levels of HULC decrease, Colorectal cancer eEF1E1 is expressed normally. EEF1E1 gene is in close proximity to HULC gene and with high EEF1E1 was found to be upregulated in rectal probability the second can mediate the expression mucinous adenocarcinoma subtype and, in general in levels of the first (Yu et al, 2017). Other authors colorectal cancers compared to normal tissues. A reported that EEF1E1 expression levels are higher in reduction of its expression level correlates with a liver cancer and that this could predict worse worst prognosis and poor survival (Hassan et al, survival although they did not tell precisely the 2018). Other studies found that normal colon mucosa cancer type (Hassan et al, 2018). expressed EEF1E1 in nearly all of the cases while EEF1E1 expression is significantly decreased in the Lung cancer majority of colorectal cancer (CRC) cases. This EEF1E1 expression levels were reported to be high suggests that the downregulation of EEF1E1 may be in small cell lung carcinoma, in squamous cell lung related to inactivation of its tumour suppressor carcinoma subtypes, and in large cell lung function and so might play a role in the development carcinoma. These high expression levels seem to be of CRC (Chen et al, 2018; Kim et al, 2011) correlated with poor overall survival (OS) and first Gastric cancer progression (FP) in lung cancers (Hassan et al, 2018). In addition, were reported some somatic In gastric cancers is found an upregulation of mutations for EEF1E1 gene in lung cancer cell lines EEF1E1 transcript and this predicts a better overall (Kim et al, 2011). survival (OS) and first progression (FP)(Hassan et al, 2018). Other studies revealed that normal gastric Lymphoma and other blood cancers mucosa expressed EEF1E1 in nearly all of the cases EEF1E1 is found to be overexpressed in Burkitt's while EEF1E1 expression is significantly decreased lymphoma and in diffuse large B-Cell lymphoma. in the majority of gastric cancer (GC) cases. This On the contrary, it is found to be downregulated in suggests that the downregulation of EEF1E1 may be marginal zone B-Cell lymphoma (Hassan et al, related to the inactivation of its tumour suppressor 2018), acute promyelocytic leukemia and chronic function and so might play a role in the development myelogenous leukemia (Gurung et al, 2015). In of GC (Kim et al, 2011). chronic myelogenous leukemia was observed some Head and neck squamous cell somatic mutations for EEF1E1 (Kim et al, 2011). In addition, EEF1E1 shows an increased expression in carcinoma (HNSC) pyothorax-associated lymphoma (PAL), a EEF1E1 is found to be overexpressed in head and lymphoma developing in long-standing neck cancers (Hassan et al, 2018). Wiest and inflammation (Nishiu et al, 2004). colleagues (Wiest et al, 2002) have found an Ovarian cancer interesting feature in the HPV16 infection in some samples of head and neck cancer in relation to It is detected that EEF1E1 is frequently upregulated EEF1E1. In detail, the integration site of E6/E7 in ovarian serous adenocarcinoma (Hassan et al, region of HPV16 falls on chromosome 6 in the 2018). proximity of some human genes included EEF1E1. Pancreatic cancer This could contribute to explain the oncogene EEF1E1 expression levels were found to be property of HPV16 or one of the oncogenesis significantly downregulated in pancreatic cancers mechanisms of head and neck cancer. However, it is (Hassan et al, 2008). still unclear if the viral integration can affect the regulation of expression of EEF1E1. Prostate cancer Kidney cancer EEF1E1 is significantly overexpressed in prostate EEF1E1 was found to be downregulated in cancer. Currently, there is not sufficient data about chromophobe renal cell carcinoma and in kidney clear cell carcinoma (Hassan et al, 2018). the prognostic significance of the upregulation of Liver cancer EEF1E1 in prostate cancer (Hassan et al, 2018). It was documented that eEF1E1 is down-regulated in hepatocellular carcinoma (HCC)(Yu et al, 2017; Du To be noted et al, 2012). In particular, there is a high relation

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HIV-1 interactions: It is reported that HIV-1 MA He Y, Yuan C, Chen L, Lei M, Zellmer L, Huang H, Liao DJ. protein interacts with EEF1E1 in human HEK293 Transcriptional-Readthrough RNAs Reflect the Phenomenon of "A Gene Contains Gene(s)" or "Gene(s) and Jurkat cell lines (Jäger et al, 2011) and that within a Gene" in the , and Thus Are Not EEF1E1 is subject to cleavage by the HIV-1 protease Chimeric RNAs Genes (Basel) 2018; 9(1). pii: E40 (Impens et al, 2012). Hu X, Yang L, Mo YY. Role of Pseudogenes in Tumorigenesis. Cancers (Basel) 2018; 10(8) References Impens F, Timmerman E, Staes A, Moens K, Ariën KK, Celestino-Soper PB, Skinner C, Schroer R, Eng P, Shenai Verhasselt B, Vandekerckhove J, Gevaert K. A catalogue of J, Nowaczyk MM, Terespolsky D, Cushing D, Patel GS, putative HIV-1 protease host cell substrates Biol Chem Immken L, Willis A, Wiszniewska J, Matalon R, Rosenfeld 2012; 393(9):915-31 JA, Stevenson RE, Kang SH, Cheung SW, Beaudet AL, Iofrida C, Melissari E, Mariotti V, Guglielmi C, Guidugli L, Stankiewicz P. Deletions in chromosome 6p22.3-p24.3, Caligo MA, Pellegrini S. Effects on human transcriptome of including ATXN1, are associated with developmental delay mutated BRCA1 BRCT domain: a microarray study BMC and autism spectrum disorders. Mol Cytogenet. 2012 Apr Cancer 2012; 12:207 5;5:17 Jäger S, Cimermancic P, Gulbahce N, Johnson JR, Chen J, Liu S, Hu X. Long non-coding RNAs: crucial McGovern KE, Clarke SC, Shales M, Mercenne G, Pache regulators of gastrointestinal cancer cell proliferation. Cell L, Li K, Hernandez H, Jang GM, Roth SL, Akiva E, Marlett Death Discov. 2018;4:50 J, Stephens M, D'Orso I, Fernandes J, Fahey M, Mahon C, Cho HY, Maeng SJ, Cho HJ, Choi YS, Chung JM, Lee S, O'Donoghue AJ, Todorovic A, Morris JH, Maltby DA, Alber Kim HK, Kim JH, Eom CY, Kim YG, Guo M, Jung HS, Kang T, Cagney G, Bushman FD, Young JA, Chanda SK, BS, Kim S. Assembly of Multi-tRNA Synthetase Complex Sundquist WI, Kortemme T, Hernandez RD, Craik CS, via Heterotetrameric Glutathione Transferase-homology Burlingame A, Sali A, Frankel AD, Krogan NJ.. Global Domains. J Biol Chem. 2015 Dec 4;290(49):29313-28 landscape of HIV-human protein complexes Nature 2011; 481(7381):365-70 Cho DI, Oak MH, Yang HJ, Choi HK, Janssen G, Kim KM. Direct and biochemical interaction between D3 Kang T, Kwon NH, Lee JY, Park MC, Kang E, Kim HH, Kang receptor and elonga on factor-1Bβγ Life Sci 2003; 73:2991- TJ, Kim S. AIMP3/p18 controls translational initiation by 3004. mediating the delivery of charged initiator tRNA to initiation complex J Mol Biol 2012; 423(4):475-81 Deineko V.V.. On ARS-interacting multifunctional protein p18 Nat Prec 2008 Kim SM, Jeon Y, Kim D, Jang H, Bae JS, Park MK, Kim H, Kim S, Lee H. AIMP3 depletion causes genome instability Du Y, Kong G, You X, Zhang S, Zhang T, Gao Y, Ye L, and loss of stemness in mouse embryonic stem cells Cell Zhang X. Elevation of highly up-regulated in liver cancer Death Dis 2018; 9(10):972 (HULC) by hepatitis B virus X protein promotes hepatoma cell proliferation via down-regulating p18 J Biol Chem 2012; Kim SS, Hur SY, Kim YR, Yoo NJ, Lee SH. Expression of 287(31):26302-11 AIMP1, 2 and 3, the scaffolds for the multi-tRNA synthetase complex, is downregulated in gastric and colorectal cancer Fan X, Qi B, Ma L, Ma F. Screening of underlying genetic Tumori 2011; 97(3):380-5 biomarkers for ankylosing spondylitis. Mol Med Rep 2019; 19(6):5263-5274 Mao M, Fu G, Wu JS, Zhang QH, Zhou J, Kan LX, Huang QH, He KL, Gu BW, Han ZG, Shen Y, Gu J, Yu YP, Xu SH, Fowles LF, Bennetts JS, Berkman JL, Williams E, Koopman Wang YX, Chen SJ, Chen Z. Identification of genes P, Teasdale RD, Wicking C. Genomic screen for genes expressed in human CD34(+) hematopoietic involved in mammalian craniofacial development Genesis stem/progenitor cells by expressed sequence tags and 2003; 35(2):73-87 efficient full-length cDNA cloning. Proc Natl Acad Sci USA 1998; 95(14):8175-80 Gao Q, Liang WW, Foltz SM, Mutharasu G, Jayasinghe RG, Cao S, Liao WW, Reynolds SM, Wyczalkowski MA, Yao L, Mirande M. The Aminoacyl-tRNA Synthetase Complex Yu L, Sun SQ; Fusion Analysis Working Group; Cancer Subcell Biochem 2017; 83:505-522 Genome Atlas Research Network, Chen K, Lazar AJ, Fields RC, Wendl MC, Van Tine BA, Vij R, Chen F, Nykter M, Nishiu M, Tomita Y, Nakatsuka S, Takakuwa T, Iizuka N, Shmulevich I, Ding L. 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Pittman YR, Kandl K, Lewis M, Valente L, Kinzy TG. Mapping the contact surfaces in the Lamin A:AIMP3 Coordination of eukaryotic translation elongation factor 1A complex by hydrogen/deuterium exchange FT-ICR mass (eEF1A) function in actin organization and translation spectrometry PLoS One 2017; 12(8):e0181869 elongation by the guanine nucleotide exchange factor eEF1Balpha. J Biol Chem 2009; 284(7):4739-47 Wiest T, Schwarz E, Enders C, Flechtenmacher C, Bosch FX. Involvement of intact HPV16 E6/E7 gene expression in Quevillon S, Mirande M.. The p18 component of the head and neck cancers with unaltered p53 status and multisynthetase complex shares a protein motif with the perturbed pRb cell cycle control. Oncogene 2002; beta and gamma subunits of eukaryotic elongation factor 1. 21(10):1510-7 FEBS Lett 1996; 395(1):63-7. Yoshihara K, Wang Q, Torres-Garcia W, Zheng S, Vegesna Shalak V, Guigou L, Kaminska M, Wautier MP, Wautier JL, R, Kim H, Verhaak RG. The landscape and therapeutic Mirande M.. Characterization of p43(ARF), a derivative of relevance of cancer-associated transcript fusions. the p43 component of multiaminoacyl-tRNA synthetase Oncogene 2015; 34(37):4845-54 complex released during apoptosis. J Biol Chem 2007; 282(15):10935-43 Yu X, Zheng H, Chan MT, Wu WK. HULC: an oncogenic long non-coding RNA in human cancer J Cell Mol Med Smeester L, Rager JE, Bailey KA, Guan X, Smith N, 2017; 21(2):410-417 GarcÕa-Vargas G, Del Razo LM, Drobná Z, Kelkar H, Stýblo M, Fry RC. Epigenetic changes in individuals with This article should be referenced as such: arsenicosis Chem Res Toxicol 2011; 24(2):165-7 Cristiano L. EEF1E1 (eukaryotic translation elongation factor 1 epsilon 1). Atlas Genet Cytogenet Oncol Tao Y, Fang P, Kim S, Guo M, Young NL, Marshall AG. Haematol. 2020; 24(11):387-395.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 395 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review

RARA (Retinoic acid receptor, alpha) Franck Vigué [email protected]

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/RARAID46.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70859/03-2020-RARAID46.pdf DOI: 10.4267/2042/70859 This article is an update of : Viguié F. RARA (Retinoic acid receptor, alpha). Atlas Genet Cytogenet Oncol Haematol 2000;(4).txt

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Review on RARA with data on DNA, on the protein encoded, and where the gene is implicated. Keywords RARA; Retinoic acid receptor, alpha; Acute promyelocytic leukaemia; M3-AML Identity HGNC (Hugo): RARA Location: 17q21.2 Other names: RAR, NR1B1, Nuclear Receptor Subfamily 1 Group B Member, Nucleophosmin- Retinoic Acid Receptor Alpha Fusion

RARA (Retinoic acid receptor, alpha) Hybridization with LSI RARA Dual Color, Break Apart Rearrangement Probe c- (Abbott Molecular, US), showing the RARA gene on RARA (17q21) in normal cells: PAC 833D9 - Courtesy 17q21.2 (red-green or a fused yellow signal - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Adriana Zamecnikova.

RARA protein and domains.

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 396 RARA (Retinoic acid receptor, alpha) Viguié F

RA, 11-cis-RA and 13-cis-RA, via an isomerase. All DNA/RNA these isoforms are members of the retinoids, acting in different tissues after linkage with specific nuclear Description protein receptors. There are two families of RA 9 exons; total gene sequence: 7450 bp. receptors, the RARs (retinoic acid receptor α, β, and Transcription γ: RARA, RARB, RARG) and the RXRs (retinoid X receptor α, β and γ: RXRA, RXRB, RXRG). RARA 2.8 and 3.6 kb transcripts. (RARα) is involved essentially in hematopoiesis, while RARγ (RARG) is assigned to the skin. To be Protein activated RARs can bind to ATRA or 9-cis-RA while RXRs bind only to 9-cis-RA (Allenby G et al., Description 1993). 462 amino acids - 6 evolutionarily conserved domains - 5 functional domains : N-terminal A/B Wild type RARA binds to DNA by its C domain, as domain (transcriptional regulation AF1), C (DNA a heterodimer with a related retinoid X receptor binding domain, contains 2 zinc fingers motifs, (RXR). The site of binding is a specific DNA necessary for binding to RARE DNA sequence), D sequence, the RA response element (RARE). The (cellular localization signal), E (-binding RARE domain is located in the promoter of target domain, transcriptional regulation AF2) and F genes, it is composed classically of two direct (function not well understood today).. repeats of a consensus sequence 5'-PuG(G/T)CA-3', separated by 1, 2 or 5 base pairs named respectively Expression DR1, DR2 and DR5 (Umesono K et al., 1991). In the RARA is expressed in hematopoietic cells. absence of ligand the AF2 domain of the RARA Localisation protein associates with corepressors NCOR2 (also called SMRT: silencing mediator of retinoid thyroid Nuclear localisation. hormones) and/or N-CoR (nuclear corepressor) which are members of a multiprotein repressor complex. In this complex SMRT and N-Cor associate with the Sin3 proteins (SIN3A and SIN3B) which then links to histone deacetylases HDAC1 and/or HDAC2. Histone deacetylation would produce a local structural modification of the chromatin with an arrest of transcription initiation (Beato M et al., 1995; Pazin MJ and Kadonaga JT, 1997; Melnick A and Licht JD, 1999). Transport of the ligands ATRA and 9-cis-RA, and their link with RAR/RXR heterodimer are facilitated by another family of receptors, CRABP1 and CRABP2 (cellular retinoic acid binding proteins) (Bastie JN et al., 2001). Retinoid structures. When the ligand reaches its target it binds to RARA Function on the AF2 domain and modifies the molecular Ligand-dependent transcription factor activated by conformation of the receptor, so that the repressor all-trans retinoic acid (ATRA), specifically involved complex dissociates from the molecule and is in hematopoietic stem cells differentiation and replaced by coactivator proteins which can bind at maturation = receptor for all-trans retinoic acid the same site (Chambon P, 1996; Wade PA and (ATRA) and 9-cis RA which are intracellular Wolffe AP, 1997). These coactivators involve metabolites of vitamine A, active in cellular TRIM24 (also called TIF1), PSMC5 (also called differentiation and morphogenesis. The gene TRIP1 or SUG1), NCOA2 (TIF2), NCOA3 (ACTR), response to RARA binding is modulated by a series NCOA1 (SRC-1), TAF4 (TAFII135), and CREBBP of co-repressors and co-activators. (CBP). PSMC5 has a DNA helicase activity, able to Retinol (vitamin A) is strictly furnished by the unwind DNA. CREBBP and NCOA3 have an nutrition. The active retinol product is the retinoic histone acetylase activity, they bind to KAT2B acid (RA) which plays a great role as modulator of (P/CAF) which is also an histone acetylase. proliferation and differentiation in numerous tissues. Consequently, when RARA binds to its ligand In target cells retinol is oxidized as retinal with the ATRA, it becomes the member of a multiprotein help of an alcohol dehydrogenase. Then retinal is complex, in association with RXR and a number of oxidized as ATRA by a retinal dehydrogenase coactivators. The result is a local histone (ALDH1A2 or RALDH). ATRA gives rise to 9-cis- reacetylation leading to the modification of

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RARA (Retinoic acid receptor, alpha) Viguié F

chromatin conformation and stimulation of arsenic trioxide (ATO) plus anthracycline transcription machinery. The activity of many genes chemotherapy (Wang Z-Y and Chen Z, 2008; Testa involved in myeloid maturation, including U and Lo-Coco F, 2016). transcription factors, may be potentially triggered by Treatment: More than 90% of complete remission this coactivator's complex, resulting in the arrest of with ATRA plus ATO. Additional gene(s) cell growth, terminal differentiation and production alterations, involving mainly FLT3, KRAS or of mature granulocytes. CMYC, are considered as progression factors (de Homology Thé H, 2018). Cytogenetics RARA shares homology with RARB and RARG, 9- cis RA receptors (RXRs) and receptors for thyroid Variant or complex t(15;17) translocation in 5% of and steroid hormones and for vitamine D3 (VDR) cases, no known prognosis implication; secondary chromosomal abnormalities in 30 to 35% of APL at Implicated in diagnosis; association with +8 in 17 to 28% of cases; other associations are rare but recurrent: del(7q), Top note del(9q), ider(17)t(15;17), +21. Rarely the t(15;17) is In oncogenesis, RARA has been primarily not detectable cytogenetically, resulting from a implicated in acute promyelocytic leukaemia (APL) cryptic molecular insertion; if the insertion is too induction, via the expression of the PML/RARA small, FISH analysis may be negative and the fusion gene. Apart from its fusion with PML, RARA molecular analysis only will be able to detect the gene may be seldom fused by translocation, with a PML-RARA transcripts. great variety of genes (Chen Z et al., 1996; Redner Hybrid/Mutated gene RL, 2002; Adams J and Nassiri M, 2015; Yan W and The crucial fusion transcript is 5'PML-3'RARA, Zhang G, 2016) and all these fusion genes contain encoded by der(15) chromosome; the counterpart the RARA C-terminal B through F domains, 5'RARA-3'PML encoded by der(17) is inconstant. encoding DNA binding, retinoid X receptor (RXR) The breakpoint in RARA gene is always located in heterodimerization, ligand binding, and co-repressor intron between A and B domains. PML gene is and co-activator interaction functions of RARA, composed of approximately 53.000 bp with 9 exons; leading invariably and specifically to the the PML protein is member of a multiprotein development of an APL. In all the variant complex composing the matrix-associated nuclear translocations the functional activity of PML is not bodies, which are dynamic nuclear components of altered showing the crucial role of RARA in the 0.1 to 1.0 m in size. PML works as a tumour leukemogenesis process. On other part it was suppressor gene, the protein is implicated in a wide observed recently that RARB or RARG, instead of variety of cellular functions: apoptosis, RARA, could exceptionally fuse with various genes, differentiation, genome stability (Bernardi R and giving rise to an APL responding poorly to ATRA Pandolfi PP, 2007; Hsu K-S and Kao H-Y, 2018). therapy (Osumi T et al., 2018; Miller CA et al.; 2018; There are three breakpoint clusters in PML gene: Chen X et al., 2019) bcr1 (70% of patients), bcr2 (10%) and bcr3 (20%), t(15;17)(q24;q21) / acute giving rise respectively to the long (L), intermediate promyelocytic leukemia (APL) --> (V) and short (S) length hybrid PML-RARA transcripts; in the 3 types of proteins the coiled-coil PML / RARA domain of PML, which is an element of the ring-B The translocation fuses the promyelocytic leukaemia box-CC/tripartite domain, is conserved; V form gene (PML) at 15q24 with RARA (Kakizuka A et would be linked to ATRA with a decreased al., 1991; de Thé H et al., 1991). sensitivity and S form would be associated to an Disease excess of secondary chromosome changes. Typical APL (or M3 AML, FAB classification), Abnormal protein approximately 98% of APL cases; arrest of the white 106 Kda fusion protein; role in the leukemogenic blood cells maturation at the promyelocytic stage process through two main pathways: 1) interference giving an accumulation of abnormal promyelocytes with the signalling pathway controlled by RARA with Auer rods and bundles (faggots); disruption of and involved in differentiation and maturation of the PODs with a microspeckeled pattern; maturation myeloid precursors (mainly dysregulation of response to all-trans retinoic acid (ATRA) therapy. retinoid-inducible genes responsible for in myeloid Prognosis differentiation). 2) disruption of the PML nuclear Immediate prognosis is impaired by intravascular bodies (PML-NBs) which control the P53 pathway disseminated coagulopathy; long term prognosis is and many other cellular functions involved in favorable with treatment combining ATRA and/or genome stability, apoptosis, cellular senescence, differentiation, angiogenesis.

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Molecular pathogenesis of APL.

In contrast with wild type RARA which only forms t(11;17)(q23;q12) / acute heterodimers with RXRA, the fusion protein PML/RARA can form homodimers through the promyelocytic leukemia --> ZBTB16 / coiled-coil domain of PML, which is the critical RARA domain for the transformation of PML/RARA into Described in Chen Z et al., 1994; Licht JD et al., an oncoprotein (Lin RJ and Evans RM, 2000; 1995; Melnick A and Licht JD, 1999; Sainty D et al., Occhionorelli M et al., 2011). 2000. ZBTB16 is also named PLZF, ZNF145. The homodimer can link to the DNA, independently Disease from RXR. The expression of PML/RARA Variant acute promyelocytic leukemia (APL) form homodimer is sufficient ex vivo to operate the with atypical cytologic aspects: intermediate cellular transformation, however the PML/RARA morphology between M2 and M3, less or not bilobed homodimer is quasi always linked in vivo to RXRA promyelocyte nucleus, no Auer rods, the which is necessary to an efficient DNA binding. hypogranular form is predominant with coarse It results in a dominant negative control of both granules, absence of faggot cells, increased number native PML and RARA functions (de Thé H et al., of hypogranular pseudo-Pelger neutrophils and 1991; Melnick A and Licht JD, 1999; Occhionorelli increased CD56 expression; generally no response to M et al., 2011). Binding of the homodimer, by the ATRA therapy; however some cases achieved a RARA domain of PML-RARA, with DNA sites remission with a treatment combining ATRA and located in the promoter region of target genes, and chemotherapy or ATRA and G-CSF; worse multimerisation owing to the coiled-coil domain of prognostic than APL with t(15;17), whatever the PML, enhances the recruitment of co repressor treatment. Found in less than 1% of APL cases. proteins and of histone deacetylases (HDACs), Cytogenetics leading to a gene repression via DNA methylation (Di Croce L et al., 2002; Martens JH et al., 2010; In some cases the translocation may be cryptic. Occhionorelli M et al., 2011). Hybrid/Mutated gene The classical consequences are a block of myeloid Native ZBTB16 (zinc finger and BTB domain differentiation at the promyelocytic stage. A second containing 16) has 7 exons, 3 alternative transcripts; activity of PML-RARA is to disrupts the PML encodes a 673 amino acids zinc finger protein, nuclear-bodies involved in many cellular containing one N-terminal POZ-BTB domain (Pox regulations, particularly TP53 activation, leading to virus and Zinc finger domain also called Broad an increase of progenitors self renewal (Bernardi R Complex, tramtrack, Bric a Brac ), one RD2 domain and Pandolfi PP, 2007; Nasr R et al., 2008). and 9 C-terminal zinc finger motifs. The native protein is involved as transcriptional

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repressor in a number of pathways during t(11;17)(q13;q12) / acute development (Liu et al., 2016). The t(11;17) results promyelocytic leukemia --> NUMA1 / in two reciprocal transcripts, encoding in the same reading frame ZBTB16/RARA and RARA/ZBTB16 RARA proteins. ZBTB16/RARA contains the same RARA Described in Wells RA et al., 1996, 1997, the third domains as in PML/RARA. variant translocation to be described. Only one case Resistance to ATRA therapy is caused by the reported to date, in a 6-month old male infant. insensibility to ATRA of the corepressors-ZBTB16- Disease /RARA complex, in which N-CoR/SMRT co Presentation as a quite classical APL who expressed, repressor proteins maintain there link with the however, multiple unexpected cutaneous lesions but ZBTB16 part of ZBTB16/RARA, even with peripheral blood smears and cellular therapeutic levels of ATRA. immunophenotype were typical of APL. Respond to t(5;17)(q35;q12) / acute promyelocytic ATRA treatment and there was no relapse at 3 years leukemia --> NPM1 / RARA after autologous bone marrow transplantation. Described in Corey SJ et al., 1994; Redner RL et al., Hybrid/Mutated gene 1996; Rush EA et al., 2013. The translocation fuses The NUMA1 gene (nuclear mitotic apparatus) the nucleophosmin gene (NPM1) with RARA. It is located at 11q13, encodes NuMA, a high molecular the second most frequent variant translocation after weight (238 kDa) coiled-coil protein component of the t(11;17)(q23;q21). Apart from NPM1/RARA the nuclear matrix at interphase and associated with two other translocation / fusion gene involve NPM1 the spindle poles during mitosis. It is involved in the in haematological neoplasms: t(2;5)(p23;q35) processes of mitosis and in the nuclear NPM1/ALK fusion in anaplastic large cell reconstructing after mitosis. NUMA1 is composed lymphoma and t(3;5)(q25;q35) NPM1/MLF1 fusion of a large coiled-col interstitial domain of in MDS and AML. Down or up regulation of NPM1 approximately 1500 amino acids involved in homo- caused by mutations lead also to solid tumors heterodimerization, encompassed with two globular (Grisendi S et al., 2006). C-terminal and N-terminal domains. The C-terminal Disease domain contains a nuclear localization signal (NLS), a microtubule binding domain (MT), a LGN binding Exceptional; expresses overall similar morphologic sequence and 4 phosphorylation sites. This complex and immunophenotypic features as classical APL; domain is necessary for localization to the nucleus respond to ATRA treatment. and mitotic spindle functioning. The N-terminal Hybrid/Mutated gene domain is required for post mitotic nuclear NPM1 encodes a nucleolar phosphoprotein mainly reassociation. Both N- and C-terminal domains involved in ribosomal particles assembly and contain DNA-binding S/TPXX motifs (Melnick A regulation of centrosome duplication. It is also and Licht JD, 1999; Radulescu AE and Cleveland implicated in the regulation of stability and activity DW, 2010). of various tumor suppressor proteins, including The t(11;17)(q13;q21) gave rise to a 2286 amino TP53. It plays a crucial role in cell growth regulation acids NUMA1/RARA fusion protein, linking in the and genomic stability. According to the same reading frame the B-F domain of RARA to the physiological or physiopathological conditions N-terminal globular and the coiled coil domains of NPM1 should be considered either as an oncoprotein NUMA1. No alternative RARA/ NUMA1 protein or as a tumor suppressor (Grisendi S et al., 2006). could be detected. NUMA1/RARA plays a role of The t(5;17) produces both NPM1/RARA and, dominant negative RA receptor. It is able to bind to inconstantly, RARA/NPM1 transcripts. Only quite the same RARE sites as PML/RARA, equally NPM1/RARA protein is responsible for APL as a homodimer or a heterodimer with RXR but more disease. As for PML/RARA and ZBTB16/RARA stable as a RXR heterodimeric complex (Dong S et fusion genes the breakpoint in RARA occurs in the al., 2003). second intron so that its B-F domain is fused to the N-terminal domains of NPM1, in the same reading der(17) / acute promyelocytic frame. The analysis of the initial published case leukemia --> STAT5B / RARA (Redner RL et al., 1996) showed two different The STAT5B/RARA fusion gene is a rare event, no breakpoint in NPM1, generating two transcripts of more than 12 cases were published in 2018. It results 2.3 kb and 2.4 kb. Both coded two proteins of 520 probably from a variable rearrangement of 17q, and 563 amino acids respectively, with the same interstitial deletion, duplication, inversion or other level of expression. These two fusion proteins had a more complex rearrangement, undetectable by RA-dependent transcriptional activity. conventional and molecular cytogenetic.

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RARA (Retinoic acid receptor, alpha) Viguié F

However FISH with a commercial RARA dual rectangular and round cytoplasmic inclusion bodies colour or break apart probe is able sometimes to give in promyelocytes. informations, mainly in case of deletion of the 3'- Patient responded to ATRA therapy but was resistant RARA sequences. In the first published case to ATO. (Arnould C et al., 1999) der(17) resulted from a Hybrid/Mutated gene duplication of the 17q21.3-q23 segment. The BCOR gene (BCL6 co repressor) located at Disease Xp11.4 encodes a 180 kDa nuclear protein which is Male predominance, only two female cases reported. a component of a polycomb complex acting as a Clinical and cytological data compatibles with transcription suppressor. variant APL or sometimes quite atypical for APL. The BCOR/RARA fusion protein has a self Very poor response to ATRA and/or ATO therapy. association capacity through its BCOR-S region and No one long term complete remission could be ankyrin-repeat domain. obtained (Zang C et al., 2018). It can also form a heterodimer with RXR to bind with Hybrid/Mutated gene RARE, acting as a dominant negative factor of The STAT5B gene (signal transducer and activator RARA transcription. of transcription 5B) is located at 17q21.2, it contains der(17) / acute promyelocytic 19 exons and a total of 5090 coding nucleotides. It is leukemia --> PRKAR1A / RARA a member of the STAT family, it encodes a 92 kD S STAT5B protein which contains STAT proteins Described in Catalano A et al., 2007. Only one case conserved domains: a N- terminal coiled coil published in a 66-year-old man. domain, a DNA binding domain, a SH2 domain and Karyotype showed only a trisomy 22. RARA break a C-terminal transactivation domain. STAT5B is a apart FISH showed a deletion of the 5'-RARA probe signal transducer and activator of transcription, on a der(17). acting in the janus kinase (JAK)-STAT signaling A dual colour PML/RARA FISH showed a split of pathway. It is activated by tyrosine-phosphorylation, the RARA signal on der(17) and normal PML permitting homo- or heteridimerization. Located signals. Later on FISH with RARA and PRKAR1A inactive in the cytoplasm, the protein is rapidly probes confirmed the split of RARA and the translocated to the nucleus after dimerization and PRKAR1A/RARA fusion on the der(17). binds to DNA to activate its target genes (Del Disease Rosario AM et al., 2012). The STAT5B/RARA The patient was investigated for fatigue and fusion protein is composed of the N- terminal coiled- anorexia. No signs of coagulopathy were observed, coil domain necessary for dimerization, the DNA hypercellular bone marrow contained 83% of binding domain, the SH2 and a part of the SH3 hypergranular promyelocytes, but without Auer rods domains of STAT5B, fused in the same reading or fagot cells. Patient responded well to ATRA and frame to the B to F domains of RARA. ATO. No alterne RARA/ STAT5B protein is produced. Hybrid/Mutated gene Like PML/RARA, STAT5B /RARA binds to RARE PRKAR1A (protein kinase A regulatory subunit1) is as a homodimer or heterodimer with RXR. It works located at 17q24.2. as a competitive inhibitor of transcriptional activity The protein is involved in the regulation of cAMP- of RARA-RXR. This inhibition depends essentially dependent PRKA enzymatic activity. on the presence of the coiled coil domain of PRKAR1A/RARA binds to a number of RARE STAT5B. sequences, either as a homodimer or as a heterodimer When this domain is absent, in transfection with RXR. experiments with modified STAT5B /RARA However, only the interaction of RXR with protein, STAT5B/RARA expresses the same PRKAR1A/RARA is critical for leukemic transcriptional activity as wild type RARA (Dong S transformation (Qiu JJ et al., 2010). and Tweardy DJ, 2002; Huret JL, 2010). t(X;17) (p11;q21) / acute t(4;17)(q12;q21) / acute promyelocytic promyelocytic leukemia --> BCOR / leukemia --> FIP1L1 / RARA RARA Described in Kondo T et al., 2008, Zamecnikova A, 2015. Seventh variant translocation to be described, Described in Yamamoto Y et al., 2000. Only two three APL cases published, however the cases reported to date, the first in a 45-year-old man FIP1L1/RARA fusion was previously reported in with a 45,-Y, t(X;17)(p11;q21) karyotype. one case of juvenile myelomonocytic leukaemia Disease (Buijs A and Bruin M, 2007). First case clinical presentation as a variant APL, with 83% of promyelocytes in a hypercellular bone Disease marrow and a coagulopathy, but with unusual

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RARA (Retinoic acid receptor, alpha) Viguié F

The first patient, a 90-year old woman, responded to One case reported in a 35-year-old APL man which ATRA therapy. did not respond to ATRA therapy. Hybrid/Mutated gene Hybrid/Mutated gene RARA breakpoint was, as expected, up side of exon The t(7;17) unbalanced translocation resulted in a 3 and it fused with exon 15 or exon 13 of FIP1 motif. fusion between exon 6 of GTF2I and common exon der (2)t(2;17)(q32;q21) / acute 3 of RARA. GTF2I protein (general transcription factor 2I) is a members of the transcription factor 2I promyelocytic leukemia --> NABP1 / family. RARA It contains a leucine zipper for homodimerization Described in Won D et al., 2013; Zamecnikova A, and a DNA binding domain. There are 4 human 2018. GTF2I isoforms which are expressed in various Disease tissues. Only one case described to date, a 59-year old man Prognosis who achieved complete remission with ATRA In APL, resistance to ATRA was studied on followed by chemotherapy and allogenic bone GTF2I/RARA-transfected HL60 cells. It showed marrow stem cells transplantation. that the resistance was associated to the interaction Hybrid/Mutated gene between GTF2I/RARA and the RING finger protein 8 (RFN8) (Yan W et al., 2019). NABP1 (nucleic acid binding protein 1) also named OBFC2A (oligonucleotides / oligosaccharide t(3;17)(q26;q21) --> FNDC3B / RARA binding fold containing 2A) is located at 2q32.3, it is Described in Cheng CK et al., 2017. involved in DNA damage response and genome stability. In the NABP1/RARA fusion gene exon 5 Disease of the NABP1 gene is fused with the exon 3 of One case in a 36-year-old man. Cytology and RARA. immunophenotype were compatible with APL and patient responded to ATRA followed by t(3;17)(26;q21) --> TBL1XR1 / RARA chemotherapy and a complete remission was Described in Chen Y et al., 2014; Zamecnikova A, obtained at day 30, however patient relapsed at 8 2018. months. Disease Hybrid/Mutated gene Fusion gene detected in a patient with a complex At the karyotypic level the translocation was the translocation t(3;17)(q26;q21), t(7;17)(q11.2;q21). same as the t(3;17)(26;q21) which produce the Three cases known to date. Response to ATRA TBLR1XR1/RARA fusion. DNA sequencing therapy. showed the FNDC3B/RARA fusion between exon Hybrid/Mutated gene 24 of FNDC3B and exon3 of RARA. Two reciprocal TBL1XR1/RARA (transducin beta-like 1 X-linked RARA-FNDC3B transcripts were detected. receptor 1) also known as TBLR1 (transducin beta- FNDC3B (fibronectin type III domain containing like protein 1-related protein). The TBL1XR1protein 3B) is implicated in protein interactions, particularly contains a LisH domain which is necessary for homo it has a role in granulocytic differentiation and it was or heterodimerization, it could be involved in the involved in an APL-like leukaemia without RARA TBL1XR1/RARA homodimerization. intervention (Wang HY et al., 2016) t(1;17)(q42;q21) --> IRF2BP2 /RARA t(3;17)(q12;q21) --> TFG / RARA Described in Yin CC et al., 2015 ; Shimomura Y et Described in Chong ML et al., 2018. al., 2016 ; Jovanovic JV et al., 2017 ; Zamecnikova A, 2017 ; Mazharuddin S et al., 2018. Disease One case published in a 16-year-old man with a Disease t(3;14;17) complex translocation. Bone marrow Four cases described in 2018, all with clinical, hypergranular promyelocytes and cytological and immunophenotypic features immunophenotype diagnosed an APL which compatibles with APL. Two patients at least responded to ATRA therapy. responded to ATRA therapy. Hybrid/Mutated gene Hybrid/Mutated gene RNA and cDNA sequencing showed a TFG/RARA Breakpoint in IRF2BP2 (interferon regulatory factor fusion. TFG (TRK-fused gene) is located at 3q12.2, 2 binding protein 2) exon 2 and in RARA intron 2. breakpoints of the fusion gene occurred in TFG exon t(7;17)(q11;q21) --> GTF2I / RARA 7 and RARA exon 3. Described in Li J et al., 2015. Non APL malignancies Disease Disease

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RARA (Retinoic acid receptor, alpha) Viguié F

Mutations in the ligand binding domain of RARA, AML patients with such a SE could be sensitive to associated with MED12 gene mutations, were RA therapy (McKeown MR et al.; 2017). frequently observed in breast fibroadenoma and t(11;17)(q23;q12) / M5 acute myeloid leukemia --> phyllode tumors (Tan J et al., 2015). KMT2A / RARA: 1 case to date (Shekhter-Levin et A super enhancer (SE) was observed at the RARA al.2000); not found in APL; belongs to the locus, in a subset of patients with AML other than MLL/11q23 leukemias APL. This SE was associated with a high RARA expression and evidences of differentiation in AML Breakpoints cell lines, leading to the hypothesis that non-APL

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Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 407 Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Gene Section Review TNIK (TRAF2 and NCK interacting kinase) Adriana Cassaro Department of Health Sciences, University of Milan, via A. Di Rudini', 8 20142, Milan (Italy); [email protected]

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/TNIKID43532ch3q26.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70860/03-2020-TNIKID43532ch3q26.pdf DOI: 10.4267/2042/70860

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract Identity The serine/threonine kinase Traf2- and Nck Other names: TRAF2 and NCK-Interacting Protein interacting kinase (TNIK), is a member of the Kinase 3 4, EC 2.7.11.1 4 52, EC 2.7.11 52, germinal center kinase (GCK) family that has been KIAA0551 4, MRT54 3 reported to have an important role in the regulation of Jun N-terminal kinase pathway (JNK) activation HGNC (Hugo): TNIK and actin cytoskeleton. It has also been demonstrated Location: 3q26.2-q26.31 that TNIK is an important activator of Wnt pathway, Local order: Starts at 171058414 and ends at where it interacts with β-catenin/TCF4 complex, 171460408 bp from pter phosphorylates TCF4 inducing the transcription of Wnt target genes. In several studies, the expression DNA/RNA of TNIK has been established to be involved in different human cancers. Description Keywords The TNIK gene size is 397827bp encoding by 33 TNIK, TRAF2 and NCK interacting kinase, TCF4, exons. This gene has 15 transcripts (splice variants), β-catenin, CTNNB1 312 orthologues, 35 paralogues (http://www.ensembl.org/).

Figure 1: Location of TNIK gene on chr3.

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Figure 2: Schematic illustration of TNIK protein domains.

The protein encoded by this gene is a TNIK-205 ENST00000459881.1 : mRNA 583, no serine/threonine kinase that functions as an activator protein of the Wnt signaling pathway. TNIK-213 ENST00000487846.1 : mRNA 573, no protein Transcription 15 transcripts variant have been found for this gene Protein (http://www.ensembl.org/). TNIK-204 ENST00000436636.7 : mRNA 9892bp, Description protein 1360aa The serine/threonine kinase Traf2- and Nck TNIK-202 ENST00000341852.10 : mRNA 4727, interacting kinase (TNIK), is a member of the protein 1276aa germinal center kinase (GCK) family, that it was TNIK-201 ENST00000284483.12 : mRNA 4059, isolated by yeast two-hybrid screening for proteins protein 1352aa that interact with TRAF2 and NCK (Fu CA et TNIK-203 ENST00000357327.9 : mRNA 3996, al.,1999). protein 1331aa It was demonstrated that TNIK regulates Jun N- TNIK-210 ENST00000470834.5 : mRNA 3972, terminal kinase pathway (JNK), the actin protein 1323aa cytoskeleton, it is an important activator of Wnt TNIK-214 ENST00000488470.5 : mRNA 3918, signaling and it is involved in in the survival of many protein 1305aa human cancer cells (Lee Y. et al., 2017). TNIK-206 ENST00000460047.5 : mRNA 3894, The gene TNIK encodes a 1360 aa protein with protein 1297aa several spliced isoforms. This protein has an N- TNIK-211 ENST00000475336.5 : mrNA 3807, terminal kinase domain, an intermediate domain and protein 1268aa an C-terminal germinal center kinase homology TNIK-209 ENST00000468757.1 : mRNA1128, (GCKH) region, later called Citron homology protein 350aa (CNH) domain (Fu CA et al.,1999; Taira K. et al., TNIK-208 ENST00000465393.1 : mRNA 750, 2004) It was observed that it shared about 90% protein 45aa amino acid identity with other two previously cloned TNIK-207 ENST00000464785.1 : mRNA 437, no GCK family member, NIK and MAPK4, in both its protein kinase and CNH domains. However, this homology TNIK-215 ENST00000496492.5 : mRNA 2736, no goes down to about 50% in the intermediate region protein suggesting potentially different signaling role for TNIK-212 ENST00000484051.5 : mRNA 1180, no these GCK proteins (Su YC. et al.,1997; Taira K. et protein al., 2004).

Figure 3: Representative images of: A) TNIK FISH on gastric cancer cells sample; B) TNIK immunostaining on CRC epithelium sample; C) TNIK Immunofluorescent staining of human cell line U-2 OS (Yu DH et al., 2014; Takahashi H et al.,2015; https://www.proteinatlas.org/)

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Figure 4: Schematic illustration of Wnt signaling activation. Binding of Wnt proteins to FZD leads to activation of CTNNB1 (β- catenin) in the cytoplasm. Subsequently, TNIK binds to active β-catenin and this complex is recruited to the nucleus, where TNIK directly phosphorylates TCF4 inducing the transcription of Wnt target genes.

Expression directly bind both TCF4 and β-catenin and phosphorylates TCF4 leading to transcriptional TNIK is ubiquitously expressed in human. It is activation of Wnt target genes. expressed with high level in brain, small intestine, This protein is also involved in the dendrite duodenum, testis, heart, normal and cancer epithelia development. NEDD4, the TNIK, and RAP2A form colon tissues. a complex that controls NEDD4-mediated Its expression it also observed in endometrium, lung, ubiquitination of RAP2A. lymph node, kidney, spleen, thyroid, urinary Ubiquitination by NEDD4 inhibits RAP2A function, bladder, gall bladder, prostate, endometrium, which reduces the activity of Rap2 effector kinases adrenal, bone marrow of the TNIK family and promotes dendrite growth (https://www.ncbi.nlm.nih.gov/) (Kawabe H. et al., 2010). Localisation Homology TNIK is mainly localized in the nucleoplasm and TNIK is conserved in human, mouse, chicken, C. cytosol (https://www.uniprot.org/) Elegans Function TNIK was discovered by Fu CA et al. in 1999, with Mutations a yeast-two-hybrid screen for interaction partners of the adapter proteins TRAF2 and NCK. Germinal Like several other GCK family members, TNIK Recently, Anazi S. et al. in 2016 have identified in 2 regulates activation of JNK pathway which is unrelated consanguineous Saudi families affected induced through the CNH domain by a yet undefined with autosomal recessive mental retardation-54 mechanism (Fu CA et al., 1999). (MRT54) the same homozygous truncating mutation TNIK overexpression also modulates the actin in the TNIK gene that results in complete loss of the cytoskeleton; through its kinase domain, inducing protein, indicating that the mutation resulted in a null disruption of F-actin structure and inhibiting cell allele. spreading (Taira K et al., 2004). TNIK protein is known to be implicated in Wnt Somatic pathway activation. Mahmoudi T. et al. in 2009, Some somatic mutations have been identified and have identified TNIK as a co-activator protein that described by COSMIC (Catalogue of Somatic interact both TCF4/β-catenin complex in the Mutation In Cancer) and they are listed mostly as proliferative cripts of mouse small intestine. substitution; their role in disease has not yet been Through in vitro assays they showed that TNIK fully elucidated.

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both silencing and TNIK inhibitor increased cell death and reduced cell growth in TNIK amplified gastric cancer cell line, but not in TNIK not amplified cell line. Difference of CRC, in gastric cancer the role of TNIK protein is independent of Wnt pathway. (Yu DH et. al., 2014) Pancreatic cancer In pancreatic cancer patients has been shown the clinical and prognostic value of TNIK. It was observed that mRNA and protein levels of TNIK in pancreatic cancer were both significantly higher than those in corresponding paratumor tissues. In addition, they revealed that patients with high expression of TNIK had a shorter overall survival (OS) and disease-free survival (DFS) than those with low expression (Zhang Y. et al., 2016).

Figure 5: Overview of the major types of mutations Prostate cancer occurring in TNIK Prostate cancer is the fifth leading cause of cancer- Implicated in related deaths in men worldwide. It was demonstrated a nuclear expression of TNIK in Mental retardation, autosomal prostate cancer primary cells and its correlation with recessive 54; MRT54 ERG expression. Interestingly, inhibition of expression and activity of TNIK in ERG positive Mental retardation autosomal recessive 54 (MRT54) prostate cancer cells reduced colony formation and is a disorder characterized by significantly below cell viability suggesting TNIK as a novel therapeutic average general intellectual functioning. MRT54 is target to the treatment of ERG positive prostate caused by homozygous mutation in the TNIK gene. cancer. (Lee RS et al., 2019) Anazi S. et al. in 2016 identified a homozygous c.538C-T transition (c.538C-T, NM_001161563) in Lung adenocarcinoma the TNIK gene, resulting in an arg180-to-ter It is known that TINK regulates both the Wnt and (R180X) substitution. This mutation causes the Smad pathways, which are both important for formation of a truncated protein resulting in a null epithelial-to-mesenchymal transition (EMT) on allele. cancer cells (Mahmoudi T. et al., 2009; Kaneko S. et Glioma al., 2011). Jiyeon Kim J. et al. in 2014, showed that KY-05009 molecule, a potent inhibitor of TNIK Glioma is the most common primary cancers of the activity reduces TGFB1 (TGF-β1=-Mediated central nervous system. NEDD4 is reported to bind Epithelial-to-Mesenchymal Transition in Human rather than ubiquitinate TNIK in regulating the Lung Adenocarcinoma A549 cell line. They ubiquitination of GTP-RAP2A in neuron observed that KY-05009 inhibitor had a double development. Wang L.et al in 2017, showed that effects on A549 cells: it is able to inhibits TGF-β1- NEDD4 plays a pivotal role in promoting the mediated Wnt signaling through inhibition of the migration and invasion of glioma cell lines U251 and kinase activity of TNIK, which phosphorylates U87 by the inhibition of the RAP2A/TNIK complex TCF4 and it inhibits TGF-β1-induced activity. phosphorylation and nuclear translocation of Colorectal cancer SMAD2 and the expression of SNAI2 (Snail) and TNIK protein is essential for the Wnt signaling TWIST1 cofactors involved in the TGF-β1-induced activation and it was demonstrated that colorectal EMT. cancer cells were highly dependent on TNIK for Breast cancer their growth (Shitashige M. et al., 2010). Masuda M et al. in 2016, showed that NCB-0846 small Breast cancer is the most common cancer in the molecule, with high inhibitory activity against woman malignant with a high percentage of TNIK, blocked Wnt signaling and presented anti chemoresistance. It was observed that RNA tumor and anti-CSC effect on CRC cells. interference assays on breast cancer cell lines led to inhibition of cell growth (Jiao X et al., 2013). Gastric cancer Li Z. et al. in 2018 through RNA-seq data showed Microarray analysis in Chinese gastric cancer that TNIK is positive regulated by transcriptional patients reported that TNIK gene is amplified in 7% coactivator WBP2 in triple negative breast cancer of samples analyzed. Moreover, it was showed that cells (TNBC). They demonstrated that WBP2 primes

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cells to response to Wnt ligands by up-regulation of cancer mechanism of dovitinib in human multiple myeloma TNIK and GPS1 in triple negative TNBC cells. IM-9 cells. Amino Acids. 2016 Jul;48(7):1591-9 WBP2 integrates JNK with Wnt signaling improving Fu CA, Shen M, Huang BC, Lasaga J, Payan DG, Luo Y. the growth of TNBC cells. TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and Multiple Myeloma regulates the cytoskeleton. J Biol Chem. 1999 Oct 22;274(43):30729-37 Multiple myeloma (MM) is a plasma cell malignancy characterized by an accumulation of Jiao X, Hooper SD, Djureinovic T, Larsson C, Wärnberg F, Tellgren-Roth C, Botling J, Sjöblom T. Gene monoclonal plasma cells in the bone marrow. It was rearrangements in hormone receptor negative breast demonstrated that silencing and pharmacological cancers revealed by mate pair sequencing. BMC Genomics. inhibition of endogenous TNIK protein suppressed 2013 Mar 12;14:165 the proliferation of MM cells and induced caspase- Kaneko S, Chen X, Lu P, Yao X, Wright TG, Rajurkar M, dependent apoptosis (Chon HJ. Et al., 2016). Kariya K, Mao J, Ip YT, Xu L. Smad inhibition by the Ste20 Moreover, inhibition of Wnt signaling by TNIK kinase Misshapen. Proc Natl Acad Sci U S A. 2011 Jul inhibitors can suppress the IL6 -induced 5;108(27):11127-32 proliferation of MM cells suggesting TNIK protein Kawabe H, Neeb A, Dimova K, Young SM Jr, Takeda M, as a target to develop new therapeutic strategies Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, against MM (Lee Y. et al., 2017). Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N. Regulation of Rap2A by the Chronic myelogenous leukemia ubiquitin ligase Nedd4-1 controls neurite development. Neuron. 2010 Feb 11;65(3):358-72 Schürch C. et al. in 2012, identified CD27 signal transduction as a new link between the immune Kim J, Moon SH, Kim BT, Chae CH, Lee JY, Kim SH. A novel aminothiazole KY-05009 with potential to inhibit system and Wnt signaling/leukemia development in Traf2- and Nck-interacting kinase (TNIK) attenuates TGF- CML. β1-mediated epithelial-to-mesenchymal transition in human It was demonstrated that the TNF receptor family lung adenocarcinoma A549 cells. PLoS One. member CD27 is present on leukemia stem cells and 2014;9(10):e110180 its bond with CD70 ligand increased expression of Lee RS, Zhang L, Berger A, Lawrence MG, Song J, Niranjan Wnt target genes in LSCs by enhancing nuclear B, Davies RG, Lister NL, Sandhu SK, Rubin MA, Risbridger GP, Taylor RA, Rickman DS, Horvath LG, Daly RJ. localization of active β-catenin and TRAF2-and Characterization of the ERG-regulated Kinome in Prostate NCK-interacting kinase (TNIK). As a consequence Cancer Identifies TNIK as a Potential Therapeutic Target. of this, they revealed an increased proliferation and Neoplasia. 2019 Apr;21(4):389-400 differentiation of LCS. Moreover, blocking CD70 by Lee Y, Jung JI, Park KY, Kim SA, Kim J. Synergistic monoclonal antibody (mAb) treatment reduced inhibition effect of TNIK inhibitor KY-05009 and receptor disease progression and prolonged survival of CML tyrosine kinase inhibitor dovitinib on IL-6-induced mice. proliferation and Wnt signaling pathway in human multiple myeloma cells. Oncotarget. 2017 Jun 20;8(25):41091- Polycystic ovarian syndrome (PCOS) 41101 Polycystic ovary syndrome (PCOS) is the most Li D, Jiao J, Zhou YM, Wang XX. Epigenetic regulation of common endocrinopathy, affecting about 10% of the traf2- and Nck-interacting kinase (TNIK) in polycystic ovary syndrome. Am J Transl Res. 2015;7(6):1152-60 reproductive-age female population. Wang XX et al. in 2014, saw that PCOS ovarian tissues showed a Li Z, Lim SK, Liang X, Lim YP. The transcriptional coactivator WBP2 primes triple-negative breast cancer cells specific methylation and expression pattern of the for responses to Wnt signaling via the JNK/Jun kinase TNIK gene. pathway. J Biol Chem. 2018 Dec 28;293(52):20014-20028 They also reported that the TNIK transcript was up- Mahmoudi T, Li VS, Ng SS, Taouatas N, Vries RG, regulated in PCOS ovarian tissues, compared with Mohammed S, Heck AJ, Clevers H. The kinase TNIK is an normal ovarian tissues, and that methylation of essential activator of Wnt target genes EMBO J 2009 Nov cg10180092 site play a key role in the regulation of 4;28(21):3329-40 TNIK transcription (Li D. et al., 2015). Masuda M, Uno Y, Ohbayashi N, Ohata H, Mimata A, It is necessary other studies to better understood the Kukimoto-Niino M, Moriyama H, Kashimoto S, Inoue T, epigenetic mechanism involved in the initiation and Goto N, Okamoto K, Shirouzu M, Sawa M, Yamada T. TNIK progression of TNIK-related PCOS. inhibition abrogates colorectal cancer stemness Nat Commun 2016 Aug 26;7:12586 References Schürch C, Riether C, Matter MS, Tzankov A, Ochsenbein AF. CD27 signaling on chronic myelogenous leukemia stem Anazi S, Shamseldin HE, AlNaqeb D, Abouelhoda M, cells activates Wnt target genes and promotes disease Monies D, Salih MA, Al-Rubeaan K, Alkuraya FS. A null progression J Clin Invest 2012 Feb;122(2):624-38 mutation in TNIK defines a novel locus for intellectual Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata disability. Hum Genet. 2016 Jul;135(7):773-8 T, Ono M, Hirohashi S, Yamada T. Traf2- and Nck- Chon HJ, Lee Y, Bae KJ, Byun BJ, Kim SA, Kim J. Traf2- interacting kinase is essential for Wnt signaling and and Nck-interacting kinase (TNIK) is involved in the anti- colorectal cancer growth Cancer Res 2010 Jun 15;70(12):5024-33

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Su YC, Han J, Xu S, Cobb M, Skolnik EY. NIK is a new Wang XX, Wei JZ, Jiao J, Jiang SY, Yu DH, Li D. Genome- Ste20-related kinase that binds NCK and MEKK1 and wide DNA methylation and gene expression patterns activates the SAPK/JNK cascade via a conserved provide insight into polycystic ovary syndrome development regulatory domain EMBO J 1997 Mar 17;16(6):1279-90 Oncotarget 2014 Aug 30;5(16):6603-10 Taira K, Umikawa M, Takei K, Myagmar BE, Shinzato M, Yu DH, Zhang X, Wang H, Zhang L, Chen H, Hu M, Dong Machida N, Uezato H, Nonaka S, Kariya K. The Traf2- and Z, Zhu G, Qian Z, Fan J, Su X, Xu Y, Zheng L, Dong H, Yin Nck-interacting kinase as a putative effector of Rap2 to X, Ji Q, Ji J. The essential role of TNIK gene amplification regulate actin cytoskeleton J Biol Chem 2004 Nov in gastric cancer growth Oncogenesis 2014 Mar 17;3:e93 19;279(47):49488-96 Zhang Y, Jiang H, Qin M, Su X, Cao Z, Wang J. TNIK serves Takahashi H, Ishikawa T, Ishiguro M, Okazaki S, Mogushi as a novel biomarker associated with poor prognosis in K, Kobayashi H, Iida S, Mizushima H, Tanaka H, Uetake H, patients with pancreatic cancer Tumour Biol 2016 Sugihara K. Prognostic significance of Traf2- and Nck- Jan;37(1):1035-40 interacting kinase (TNIK) in colorectal cancer BMC Cancer 2015 Oct 24;15:794 This article should be referenced as such: Wang L, Zhu B, Wang S, Wu Y, Zhan W, Xie S, Shi H, Yu Cassaro A. TNIK (TRAF2 and NCK interacting kinase). R. Regulation of glioma migration and invasion via Atlas Genet Cytogenet Oncol Haematol. 2020; modification of Rap2a activity by the ubiquitin ligase 24(11):408-413.

Nedd4-1 Oncol Rep 2017 May;37(5):2565-2574

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Gene Section Review

TPH1 (tryptophan hydroxylase 1) Rafig Gurbanov, Sevinç Karaçam Bilecik Şeyh Edebali University, Department of Molecular Biology and Genetics Bilecik Şeyh Edebali University, Biotechnology Application and Research Center; [email protected] (RG); Bilecik Şeyh Edebali University, Department of Biotechnology, Bilecik Şeyh Edebali University, Biotechnology Application and Research Center; [email protected] (SK)

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/TPH1ID51272ch11p15.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70861/03-2020-TPH1ID51272ch11p15.pdf DOI: 10.4267/2042/70861

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Identity Tryptophan hydroxylase 1 gene (TPH1) encodes a Other names: TRPH, TPH, TPRH rate-limiting in the biosynthesis of the HGNC (Hugo): TPH1 (tryptophan hydroxylase 1) monoamine . Location 11p15.1 TPH1 is expressed in peripheral tissues such as the heart, lung, kidney, duodenum and adrenal gland, as Local order: shown in Chromosome 11 - well as in female reproductive tissues. NC_000011.10 Reference GRCh38.p13 Primary The mutations in this gene have been associated with Assembly. various diseases with high risk, including, schizophrenia, somatic anxiety, anger-related DNA/RNA features, bipolar disorder, suicidal behavior, and several addictions. Description Keywords The gene spans a region of 29 kilobases (kb) and consists of 11 exons. Tryptophan hydroxylase 1, Alzheimer's Disease, Serotonin, Intestine, Inflammation, Suicide, Transcription Schizophrenia, Bipolar disorder The gene has 4 transcripts (Table 1).

Figure 1. Genomic location of TPH1 gene (Chromosome 11 - NC_000011.10 Reference GRCh38.p13 Primary Assembly)

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RefSeq Name Transcript ID bp Protein Translation ID Biotype CCDS UniProt Flags Match TPH1- Protein TSL:1GENCODE

ENST00000250018.6 5325 444aa ENSP00000250018.2 CCDS7829 P17752 - 201 coding basicAPPRIS P1 TPH1- Protein CDS 3'

ENST00000528338.1 556 165aa ENSP00000436081.1 - E9PR49 - 204 coding incompleteTSL:3 Nonsense TPH1-

ENST00000417164.5 1138 206aa ENSP00000403831.1 mediated - E7EMX4 - TSL:1 202 decay TPH1- No

ENST00000525406.1 461 - lncRNA - - 203 protein - TSL:5

Table 1. Transcripts of the human TPH1 gene (Ensemble, GRCh38: CM000673.2).

Single nucleotide polymorphisms (SNPs) found in the human TPH1 gene were given in Table 2.

SNP name (Genomic Position in SNP ID PCR primers and short-extension probe localization) the gene F: 5'-ctgttcttttggtgtcctc-3' 5'flankingSNP1 (T- 5' flanking SNP000574351 R:5'-gctcctggcacttaacata-3' 1721G) region P: 5'-taatttctttcatgagtattttatagtt F: 5'-ctgttcttttggtgtcctc-3' 5'flankingSNP2 (A- 5' flanking SNP000574353 R: 5'-gctcctggcacttaacata-3' 1067G) region P: 5'-ttttttgctgagtatggatgtactttaaagctcagga F: 5'-cgataataggcgttatcttg-3' 5'flankingSNP3 (G- 5' flanking SNP000574354 R: 5'-ctcaatctctgcgtgtatct-3' 347T) region P: 5'-tcaggactgggctattaaatagcccagaagcacagaga F: 5'-taattatcctccctccaagt-3' R: 5'- Intron 1 in1SNP1 (T3804A) rs623580 cttacccattcaattaccac-3' (exon 1c) P: 5'-agagtatgggcgacgttgtccta F: 5'-tgctcttatatgtcttttcaagt-3' in2SNP1 (G7465A) Intron 2 rs684302 R: 5'-gagagatggagcaaaacac-3' P: 5'-ttaaataaaatacctgtatgtcttcttccatca F: 5'-tcaggaaaacagaagggta-3' in3SNP1 (A12517C) Intron 3 rs211105 R: 5'-ggtaaattgccctatttctaa-3' P: 5'-aggtggcaaagacaaatgatttctaagatcttttccatcggc F: 5'-gggaagaaattatgtaagtgg-3' in6SNP1 (C18626G) Intron 6 rs2237907 R: 5'-gaaatgttccatatctgtgc-3' P: 5'-ttgtaatgcacacaaaactgaaagctgatctcttagggtctggagc CF: 5'-acccacctacactttcctc-3' CR: 5'- taattgacaacctattaggttc-3' in7SNP1 (A20004C)d Intron 7 rs1800532 AR: 5'-agcacatgtgaagcatttag-3' AF: 5'-cctatgctcagaatagcagctct-3' F: 5'-cacttgaatatcacagtccatc-3' 3'UTRSNP1 (C27224T) 3' UTR rs2108977 R: 5'-gcttacagtagatttccttgc-3' P: 5'-tacatttgatggtaaatagatgctagctaatct F: 5'-cacttgaatatcacagtccatc-3' 3'UTRSNP2 3' UTR New R: 5'-gcttacagtagatttccttgc-3' (A27237G) P: 5'-aactataaatcagataatcaata

Table 2. Single nucleotide polymorphisms (SNPs) of the human TPH1 gene (Lai et al. 2005).

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Group (Total Number) Genotype (frequency) Allele (frequency) Marker 1-1 1-2 2-2 χ2 p value 1 2 χ2 p value T-1721G N(94) 54(.57) 37(.39) 3(.03) 2.72 0.248 145(.77) 43(.23) 0.36 0.548 P(92) 53(.58) 31(.34) 8(.09) 137(.75) 47(.26) A-1067G N(90) 53(.59) 34(.38) 3(.03) 1.62 0.446 140(.78) 40(.22) 0.74 0.389 P(92) 51(.55) 34(.37) 7(.08) 136(.74) 48(.26) G-347T N(102) 58(.57) 43(.42) 1(.01) 0.048 0.976 159(.78) 45(.22) 0.037 0.847 P(94) 52(.55) 41(.44) 1(.01) 145(.77) 43(.23) T3804A N(101) 56(.55) 38(.38) 7(.07) 2.17 0.304 152(.74) 52(.26) 0.015 0.946 P(96) 49(.51) 44(.46) 3(.03) 142(.74) 50(.26) G7465A N(100) 31(.31) 43(.43) 26(.26) 0.46 0.793 105(.53) 95(.48) 0.439 0.508 P(74) 25(.34) 33(.45) 16(.22) 83(.56) 65(.44) A12517C N(101) 58(.57) 39(.39) 4(.04) 0.232 0.890 155(.77) 47(.23) 0.207 0.649 P(96) 58(.60) 35(.37) 3(.03) 151(.79) 41(.21) C18626G N(100) 28(.28) 47(.47) 25(.25) 1.24 0.538 103(.52) 97(.49) 0.392 0.531 P(71) 25(.35) 28(.39) 18(.25) 78(.55) 64(.45) A20004C N(102) 40(.39) 45(.44) 17(.17) 1.726 0.422 125(.61) 79(.39) 1 795 0.18 P(89) 29(.32) 39(.44) 21(.24) 97(.54) 81(.46) C27224T N(95) 31(.33) 49(.52) 15(.16) 3.58 0.167 111(.58) 79(.42) 2.13 0.144 P(80) 23(.29) 35(.44) 22(.28) 81(.51) 79(.49) A27237G N(95) 49(.52) 40(.42) 6(.06) 0.57 0.751 138(.73) 52(.27) 0.677 0.411 P(78) 37(.47) 34(.44) 7(.09) 107(.69) 49(.34)

Table 3. The genotypic and allelic distribution of the TPH1 gene (Lai et al. 2005). N indicates the matched normal controls, P indicates the bipolar patients. 1 represents the major allele and 2 the minor allele

The genotypic and allelic distribution of the TPH1 TPH1 gene is expressed in peripheral tissues such as gene is listed in Table 3. heart, lung, kidney, duodenum and adrenal gland and female reproductive tissues Protein (http://www.proteinatlas.org). Description Function Size: 444 amino acids; Molecular mass: 50985 Da; Remarkably, about 90% of the total serotonin of the Cofactor: Fe (2+); Xref=ChEBI: CHEBI: 29033; human body is found in neuroendocrine Quaternary structure: Homotetramer enterochromaffin cells (EC) in the human Protein properties for TPH1 Gene: TPH1 is a rate- gastrointestinal (GI) tract, where it is used to regulate limiting enzyme in the biosynthesis of serotonin. It bowel movements (Lukiw and Rogaev, 2017). The catalyzes the biotin-dependent monooxygenation of mouse mammary glands stimulated by prolactin tryptophan to 5-hydroxytryptophan (5HTP), then (176760) express the genes necessary for serotonin decarboxylates to form the neurotransmitter biosynthesis, including TPH1 (Matsuda et al. 2004). serotonin. The gene is localized on the human The TPH1 mRNA increased during pregnancy and chromosome 11p15.3-p14, is about 29 kb long and lactation, and serotonin was detected in breast contains 11 exons (Craig et al. 1991). Jonsson et al. epithelium and milk. It has been observed that (1997) identified single nucleotide polymorphisms serotonin suppresses beta-casein (115460) (SNPs) A218C (rs1800532) and A779C (rs1799913) expression and causes contraction of breast alveoli. in intron 7 of the TPH1 gene. Mutations in this gene Accordingly, Matsuda et al. (2004) concluded that have been associated with high risk for various autocrine-paracrine serotonin signaling is an diseases and disorders such as schizophrenia, important regulator of breast homeostasis and early somatic anxiety, anger-related features, bipolar evolution (Matsuda et al. 2004). disorder, suicidal behavior, and several addictions (https://www.ncbi.nlm.nih.gov/gene). Expression

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Figure 2. The possible mechanisms for microbial regulation of tryptophan and 5HT release (Simplified from Gheorghe et al. 2019).

The liver is an organ that can regenerate its volume inhibiting serotonin production (Yadav et al. 2008). after major tissue loss. Lesurtel et al. (2006) showed Enterochromaffin cells (EC) synthesize intestinal that mouse thrombocytopenia leads to the inhibition serotonin (5HT). LRP5 controls 5HT synthesis by of cellular proliferation in the liver (Lesurtel et al. negatively regulating TPH1 expression in these 2006). cells. When 5HT is released in the blood, it Thrombocytes are the main carriers of serotonin in negatively regulates bone formation during bone the blood. In thrombocytopenic mice, a serotonin remodeling process (Ducy and Karsenty, 2010). agonist has been observed to regenerate liver Since 5HT is produced in the gut, its effects on the proliferation (Gershon and Tack, 2007). The intestinal microbiota are inevitable. There is a expression of HT2A (182135) and HT2B (601122) significant difference in the composition of the gut serotonin receptor subtypes has been observed to microbiota depending on whether the TPH1 is increase in the liver after hepatectomy. Antagonists knocked out and whether the progenitors are of these receptors have been shown to inhibit liver heterozygous or homozygous for this gene. Besides, regeneration. there is evidence that 5HT directly modulates the Liver regeneration has also been disrupted in mice growth of commensal bacteria (Kwon et al. 2019). lacking TPH1, the rate-limiting enzyme for the The combination of microbial and host synthesis of peripheral serotonin. Since gastrointestinal metabolism of tryptophan is likely thrombocytes contain most of the circulating an important factor in the systemic availability of serotonin, and serotonin is released by thrombocyte tryptophan, as well as levels of indoles, kynurenine aggregation, inactivation of TPH1 function is and local 5HT (Roager and Licht, 2018). The assumed to lead to severe blood clotting defects possible mechanisms for microbial regulation of (Gershon and Tack, 2007). tryptophan and 5HT release are shown in Figure 2 Loss- and gain-of-function mutations in mouse low- (Gheorghe et al. 2019). density lipoprotein receptor-related protein 5 ( LRP5) gene affected bone formation, leading to Mutations osteoporosis and increased bone mass, respectively. Yadav et al. (2008) described the TPH1 as the most Note over-expressed gene in LRP5 - / - mice and The main mutations in the human TPH1 gene were concluded that LRP5 suppresses bone formation by given in Table 4.

Missense/nonsense mutation HGMD HGVS Accessi amino HGVS Phenotyp HGMD codon change (protein Variant class Reference Source on acid (nucleotide) e ) change

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Attention Disease- PubMe deficit Halmøy CM109 Lys54Gl causing d AAA-CAA c.160A>C p.K54Q hyperacti (2010) Arch Gen 141 n mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Attention Disease- PubMe deficit Halmøy CM109 Arg142C p.R142 causing d CGT-TGT c.424C>T hyperacti (2010) Arch Gen 142 ys C mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Attention Disease- PubMe deficit Halmøy CM109 Arg145T causing d CGA-TGA c.433C>T p.R145* hyperacti (2010) Arch Gen 143 erm mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Attention Disease- PubMe deficit Halmøy CM109 Val177Il causing d GTA-ATA c.529G>A p.V177I hyperacti (2010) Arch Gen 149 e mutations 20921 vity Psychiatry 67:1033 (DM) ? 119 disorder Attention Disease- PubMe deficit Halmøy CM109 Leu274Il causing d CTC-ATC c.820C>A p.L274I hyperacti (2010) Arch Gen 145 e mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Attention Disease- PubMe deficit Halmøy CM109 Ala300T p.A300 causing d GCT-ACT c.898G>A hyperacti (2010) Arch Gen 146 hr T mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Disease- Mood PubMe Ungar (2018) Am J CM187 Arg395H p.R395 causing dysregula d CGT-CAT c.1184G>A Med Genet 494 is H mutations tion 29696 A 176:1432 (DM) ? disorder 773 Attention Disease- PubMe deficit Halmøy CM109 Ile410As causing d ATC-AAC c.1229T>A p.I410N hyperacti (2010) Arch Gen 144 n mutations 20921 vity Psychiatry 67:1033 (DM) 119 disorder Splicing mutation HGMD HGVS Accessi amino HGVS(nucleoti (dbSNP Phenoty Sourc HGMD codon change Variant class Reference on acid de) number pe e change ) Disease- Depressi PubMe Tsai CS0343 not yet rs18005 associated on, d IVS6 ds C-A +221 c.803+221C>A (1999) Neuroreport 23 available 32 polymorphisms associatio 10716 10:3773 (DP) n with 208 Regulatory mutation HGMD HGVS Accessi amino HGVS (dbSNP Phenoty Sourc HGMD codon change Variant class Reference on acid (nucleotide) number pe e change ) GGGCTATTAAATAGCCC Irritable A bowel GAAGCACAGAGA(T- syndrome Disease- Grasberger(2013) A PubMe G)GT , CR1314 not yet rs71309 associated m J d GTGGGAGGTGGGGGGAT not yet available diarrhoea 899 available 29 polymorphisms Gastroenterol 108:1 24060 T predomin (DP) 766 757 CTTGCTTTGG ant, -5854 relative to initiation associatio codon n with Small deletion Accessi HGMD HGVS Phenoty Sourc HGMD codon change HGVS Variant class Reference on amino (dbSNP pe e

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acid number change ) Attention Disease- deficit Demontis (2016) J PubMe CD1668 CAGATACATGactTCAGTT not yet c.*1342_*1344d rs60273 causing hyperacti Am Acad Child d 98 CTTA non-coding region available elACT 374 mutations vity Adolesc 27238 (DM) ? disorder, Psychiatry 55:521 071 persistent

Table 4. Mutations of the human TPH1 gene (http://www.hgmd.cf.ac.uk)

associated with increased suicide attempts (Galfalvy Implicated in et al. 2009). A relationship between the C allele of A218C and suicidal behavior (SB) was found only in Breast Cancer people over 65 years of age (Stefulj et al. 2006). A TPH1 was analyzed in histological samples to learn significant relationship between suicide risk and about the possible relationship between changing AA218C SNP allele has been reported in Caucasian 5HT synthesis and human breast cancer progression. populations (Bellivier et al. 2004). There is a strong TPH1 is evenly distributed in the epithelial stroma in relationship between SB and A779C / A218C normal breast tissue and epithelial TPH1 is markedly polymorphisms in both European and Asian stained. Compared to healthy breast cell lines, TPH1 populations (Mirkovic et al. 2016). staining intensity increased significantly in The prevalence of TPH1 A218C polymorphism was cancerous cell lines (Pai et al. 2009). evaluated in a Turkish population and a significant Alzheimer's disease (AD) relationship was found between the A allele and SB (Beden et al. 2016). It was observed that the amount of serotonin It was shown that not only the AA genotype but also increased 4 times in raphe cell bodies and decreased the CC genotype was significantly associated with 0.4-fold in amygdala synaptic ends in Alzheimer's suicide risk and depression (Zalsman et al. 2001). disease (AD) cases compared to controls. As a result On the other hand, some studies have reported that of the accumulation of oxidative metabolites of A218C genotypes are not related to the suicide serotonin and reduced transport of TPH to the axon attempt. terminals, TPH and its products are accumulated in A multi-center case-control study and meta-analysis the perikarya of raphe neurons, which may lead to showed that the A218/A779 locus increased the degeneration of serotonergic neurons in AD sensitivity to schizophrenia and contributed to (Lukiw and Rogaev, 2017). In one study, fifty psychiatric disorders characterized by high suicide percent of patients showed agitation/aggression in rates rather than affecting suicide (Beden et al. response to the NPI screening question. A significant 2016). relationship was observed between Although it was not associated with SB, there was a agitation/aggression in male subjects carrying the C significant relationship between bipolar disorder allele of the TPH1 gene. A218C polymorphism in (BPD) and small alleles of A218C in individuals this gene is linked to aggression and irritability in with psychiatric disorders (Beden et al. 2016). men. Given this, it was concluded that the agitated and aggressive behavior in AD is associated with the Schizophrenia polymorphic variation in the TPH1 gene in men. A study conducted with 837 Scandinavian According to these results, TPH (TPH1, chr11p15.1, schizophrenic patients and 1473 healthy individuals and TPH2, chr12q21.1) gene is considered as one of revealed that three of the five SNPs tested are the six genes frequently seen in AD and aggression associated with schizophrenia sensitivity including (Lukiw and Rogaev, 2017). A218C and A779C polymorphisms (Saetre et al. 2010). Suicidal behavior (SB) However, it has been shown that there is no Three polymorphisms of the TPH1 gene, a potential difference in the allele frequencies of these loci GATA transcription factor binding site A218C, among people who have attempted suicide at least A779C located in intron 7, and A6526G located in once and have no history of a suicide attempt (Saetre the promoter region, were studied in patients with et al. 2010). suicide attempts (Mirkovic et al. 2016). The A allele Although TPH1 is expressed mainly in peripheral of A218C was found to be more common in suicide tissues, its variants have been reported to be attempts than in patients who did not attempt suicide frequently associated with psychiatric disorders. The (Mirkovic et al. 2016). AA genotypes in the intron 7 TPH1 gene, shown in Figure 3, is a strong candidate and promoter region were gene for schizophrenia (Halmøy et al. 2010).

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allele have been shown to have more aggressive hostility but slightly lower neurotic hostility (New et al. 1998). A higher level of impulsivity was found in tests that focused on neurotic hostility for LL homozygous individuals (Hennig et al. 2005). Genetic studies show that the polymorphism in both alleles (L and U) of the TPH1 gene is associated with human aggression, but each allele is associated with a different type of aggression (Quadros et al. 2010). Major depressive disorder (MDD) The frequency of TPH1 C allele and CC homozygous in patients with Major depressive disorder (MDD) was higher than healthy individuals with the same genotype. According to the results of the verbal aggression and aggression questionnaire, TPH1 CC homozygotes in the MDD group scored significantly higher than the A carrier genotypes. It has been revealed that there is a relationship between the frequency of this polymorphism, aggression, and MDD (Frodl, 2016). Vitamin D activates a series of processes that are critical for maintaining normal healthy neurons, also preventing the onset of depression. Figure 3. Representation of TPH1 and other Where vitamin D enters the nucleus, it joins with the Schizophrenia-associated candidate genes (green-colored) located on Chromosome 11 retinoid X receptor (RXR) and then binds to the (http://www.szgene.org/chromo.asp?c=11). vitamin D response element (VDRE) found on a large number of genes. Aggressive Behavior Eventually, Ca2+ homeostasis is maintained by The A218C and A779C SNPs (usually called U/top inducing the expression of the calcium-binding and L/bottom alleles) found in the intron of the TPH1 proteins (calbindin and parvalbumin), SLC8A1 gene are associated with different aggression (Na2+/Ca2+ exchanger1 NCX1) and cell membrane evaluated by interview and self-reporting Ca2+ ATPase (PMCA) pump (ATP2B1 to 4 genes). questionnaires (Rujescu et al. 2002). Lower Besides, vitamin D regulates Ca2+ levels by reducing cerebrospinal fluid (CSF) 5-Hydroxyindoleacetic the expression of the voltage-dependent calcium acid (5-HIAA) levels were observed in healthy men channel CaV1.2. with the U allele (Jonsson et al. 1997), while the In this case, TPH1 is suppressed and serotonin lowest CSF 5-HIAA levels were observed in LL formation is controlled by increasing the TPH2 level. carriers diagnosed with antisocial alcoholism Reduced expression of inflammatory cytokines (Nielsen et al. 1994). Both U and L alleles were diminishes inflammation as well (Figure 4). By thought to be associated with different types of binding to its receptor ( VDR), vitamin D also aggressiveness (Quadros et al. 2010). Individuals regulates the expression of many mitochondrial with a UU allele have been shown to have more proteins that maintain mitochondrial respiration aggressive hostility but slightly lower neurotic (Berridge, 2017). hostility (New et al. 1998). Individuals with a UU

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Figure 4. Vitamin D signaling affecting TPH1 expression in depression (Simplified from https://www.wikipathways.org/index.php/Pathway:WP4698). Somatoform Disorders Bipolar Disorder (BPD) Genes in the serotonergic hypofunction and Emotional disorders (MDD and BPD) and alcohol serotonergic pathway were thought to be associated dependence are common psychiatric disorders. Nine with symptoms of somatoform disorders (Frodl, studies involving 1951 cases and 2161 control 2016). subjects were conducted to investigate the This hypothesis has been studied using a variety of relationship between TPH1 A218C polymorphism serotonin-related gene polymorphisms to determine and BPD risk (Chen et al. 2012). Of these, 4 studies whether the undifferentiated somatoform disorder is with 416 cases and 596 control subjects were associated with specific serotonin-related gene conducted in Asians, whereas 5 studies with 1535 pathways. 102 patients with the undifferentiated cases and 1565 controls were conducted in somatoform disorder and 133 Caucasians. A nominally significant relationship Healthy individuals were examined. was observed in the homozygous model of Asian It was emphasized that patients with undifferentiated populations and homozygous and recessive models somatoform disorder had a higher frequency of of Caucasian populations. It was found that the TPH1 (A218C) C-allele than healthy controls, but relationship between this polymorphism and the risk this difference was not significant after Bonferroni of BPD and alcohol dependence varies according to correction. ethnicity, and the 218A variant homozygous These findings indicate that serotonin-related gene genotype is an important risk factor for BPD and pathways are unlikely to be genetic risk factors for alcohol dependence in the Caucasians (Chen et al. the undifferentiated somatoform disorder (Frodl, 2012). A significant relationship has been reported 2016). between A218C polymorphism of TPH1 intron 7 Middle Insomnia and BPD in the French population (Lai et al. 2005). There was a positive relationship between BD and A study found a relationship between TPH1 and TPH1 polymorphism (rs1800532) in CC genotype, middle insomnia. The serotonergic pathway plays an but no relation was found between other genotypes important role in the regulation of circadian rhythm, and alleles (Hormozi et al. 2019). sleep, and wakefulness. Serotonergic axon release is high during wakefulness, decreases during non-rapid Inflammation, Crohn's Disease (CD), eye movement (NREM) sleep, and is absent during and Inflammatory Bowel Disease rapid eye movement (REM) sleep (Ursin R, 2002). TPH activity is most abundant in brain raphe, gut, (IBD) and pineal gland where N-acetyltransferase converts TPH1 catalyzes serotonin biosynthesis in EC, the serotonin to melatonin (Patel et al. 2004). Therefore, main source of 5HT (Shajib et al. 2019). The the polymorphism of TPH1 may affect the synthesis secreted 5HT regulates gut functions through a of serotonin and melatonin, so that depressed variety of 5HT receptor (5HTR) families. In patients with this polymorphism are more prone to inflammatory bowel disease (IBD), the mucosal middle insomnia (Myung et al. 2012). 5HT signal is altered, including upregulated EC cell numbers and 5HT levels. The two major forms of

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IBD are Crohn's disease (CD) and ulcerative colitis Craig SP, Boularand S, Darmon MC, Mallet J, Craig IW. (UC) which are described by long-lasting and Localization of human tryptophan hydroxylase (TPH) to chromosome 11p15.3----p14 by in situ hybridization. recurrent inflammatory lesions throughout the Cytogenet Cell Genet. 1991;56(3-4):157-9 digestive tract (Shajib et al. 2019). Through TPH1, Demontis D, Lescai F, Børglum A, Glerup S, Østergaard EC produces 5HT from dietary tryptophan (Shajib SD, Mors O, Li Q, Liang J, Jiang H, Li Y, Wang J, Lesch KP, and Khan et al. 2015). This 5HT can then be released Reif A, Buitelaar JK, Franke B. Whole-Exome Sequencing into the intestinal lumen and surrounding tissue that Reveals Increased Burden of Rare Functional and can enter the bloodstream through the dense Disruptive Variants in Candidate Risk Genes in Individuals With Persistent Attention-Deficit/Hyperactivity Disorder. J capillary bed of lamina propria (Shajib et al. 2019). Am Acad Child Adolesc Psychiatry. 2016 Jun;55(6):521-3 5HT has been evaluated in IBD and animal colitis models. TPH1-deficient mice have reduced 5HT Ducy P, Karsenty G. The two faces of serotonin in bone biology. J Cell Biol. 2010 Oct 4;191(1):7-13 content in the gut and low inflammatory cytokine production has been observed (Ghia et al. 2009). Frodl T. Do (epi)genetics impact the brain in functional Besides, pharmacological blocking of peripheral neurologic disorders? Handb Clin Neurol. 2016;139:157- 165 5HT synthesis reduced the severity of both chemical and infection-related gut inflammation. In colon Galfalvy H, Huang YY, Oquendo MA, Currier D, Mann JJ. Increased risk of suicide attempt in mood disorders and biopsy samples from CD patients, TPH1, HTR3A, TPH1 genotype J Affect Disord 2009 Jun;115(3):331-8 mucosal HTR4, and HTR7 expressions were upregulated, whereas serotonin transporter (5HTT) Gershon MD, Tack J. The serotonin signaling system: from basic understanding to drug development for functional GI expression was downregulated in inflammation. disorders Gastroenterology 2007 Jan;132(1):397-414 Besides, colonic TPH1 expression was found to be Gheorghe CE, Martin JA, Manriquez FV, Dinan TG, Cryan significantly higher in inflamed areas compared to JF, Clarke G. Focus on the essentials: tryptophan non-inflamed areas and controls (Shajib et al. 2019). metabolism and the microbiome-gut-brain axis Curr Opin Other important factors such as gut microbiota, may Pharmacol 2019 Oct;48:137-145 also affect host 5HT production in IBD. The role of Ghia JE, Li N, Wang H, Collins M, Deng Y, El-Sharkawy RT, gut microbiota in 5-HT production, via the Côté F, Mallet J, Khan WI. Serotonin has a key role in regulation of TPH1, has been shown (Yano et al. pathogenesis of experimental colitis Gastroenterology 2015). The increase in TPH1 expression was thought 2009 Nov;137(5):1649-60 to be associated with dysbiosis observed in IBD. In Grasberger H, Chang L, Shih W, Presson AP, Sayuk GS, particular, a study showed that a 5HT increase due to Newberry RD, Karagiannides I, Pothoulakis C, Mayer E, 5HTT deficiency was associated with dysbiosis. As Merchant JL. Identification of a functional TPH1 polymorphism associated with irritable bowel syndrome a result, CD and inflammation are associated with bowel habit subtypes Am J Gastroenterol 2013 increasing the mucosal 5HT signal, characterized by Nov;108(11):1766-74 the upregulation of TPH1 expression and Halmøy A, Johansson S, Winge I, McKinney JA, Knappskog downregulation of 5HTT expression (Shajib et al. PM, Haavik J. Attention-deficit/hyperactivity disorder 2019). Furthermore, high expression of IL13, a symptoms in offspring of mothers with impaired serotonin cytokine associated with increased 5HT production, production Arch Gen Psychiatry 2010 Oct;67(10):1033-43 is noteworthy. Increased 5HT availability due to its Hennig J, Reuter M, Netter P, Burk C, Landt O. Two types increased production and impaired clearance is of aggression are differentially related to serotonergic thought to play an important role in maintaining activity and the A779C TPH polymorphism Behav Neurosci 2005 Feb;119(1):16-25 intestinal inflammation and associated symptoms (Shajib et al. 2019). Hormozi M, Zarei F, Rasouli A, Salimi S, Taji O, Narooie- Nejad M.. Association study of TPH1 (rs1800532) and TPH2 (rs4570625) Polymorphisms in Type 1 Bipolar References Disorder in Iran Gene Cell Tissue. In Press(In Press):e86109. Beden O, Senol E, Atay S, Ak H, Altintoprak AE, Kiyan GS, Petin B, Yaman U, Aydin HH. TPH1 A218 allele is Jönsson EG, Goldman D, Spurlock G, Gustavsson JP, associated with suicidal behavior in Turkish population. Leg Nielsen DA, Linnoila M, Owen MJ, Sedvall GC. Tryptophan Med (Tokyo). 2016 Jul;21:15-8 hydroxylase and catechol-O-methyltransferase gene polymorphisms: relationships to monoamine metabolite Bellivier F, Chaste P, Malafosse A. Association between the concentrations in CSF of healthy volunteers Eur Arch TPH gene A218C polymorphism and suicidal behavior: a Psychiatry Clin Neurosci 1997;247(6):297-302 meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2004 Jan 1;124B(1):87-91 Kwon YH, Wang H, Denou E, Ghia JE, Rossi L, Fontes ME, Bernier SP, Shajib MS, Banskota S, Collins SM, Surette Berridge MJ. Vitamin D and Depression: Cellular and MG, Khan WI. Modulation of Gut Microbiota Composition by Regulatory Mechanisms. Pharmacol Rev. 2017 Serotonin Signaling Influences Intestinal Immune Response Apr;69(2):80-92 and Susceptibility to Colitis Cell Mol Gastroenterol Hepatol Chen D, Liu F, Yang C, Liang X, Shang Q, He W, Wang Z. 2019;7(4):709-728 Association between the TPH1 A218C polymorphism and Lai TJ, Wu CY, Tsai HW, Lin YM, Sun HS. Polymorphism risk of mood disorders and alcohol dependence: evidence screening and haplotype analysis of the tryptophan from the current studies. J Affect Disord. 2012 Apr;138(1- hydroxylase gene (TPH1) and association with bipolar 2):27-33

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XIAP (X-linked inhibitor of apoptosis) Catarina Sofia Reis Silva, Gabriel Henrique Barbosa, Paola Cristina Branco, Paula Christine Jimenez, João Agostinho Machado-Neto, Letícia Veras Costa-Lotufo Department of Pharmacology, Institute of Biomedical Sciences of the University of Sao Paulo, Sao Paulo, Brazil (CSMRS, PCB, JAMN, LVCL); Department of Marine Science, Institute of Marine Sciences, Federal University of Sao Paulo, Santos, Brazil (GHB, PCJ); [email protected], [email protected]. [email protected], [email protected], [email protected], [email protected]

Published in Atlas Database: March 2020 Online updated version : http://AtlasGeneticsOncology.org/Genes/XIAPID796chXq25.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/70862/03-2020-XIAPID796chXq25.pdf DOI: 10.4267/2042/70862

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2020 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Gastric cancer; Head and neck squamous cell Abstract carcinoma; Kidney cancer; Leukemia; Liver cancer; X-linked inhibitor of apoptosis (XIAP), also referred Lung cancer; Lymphoma; Medulloblastoma; to as BIRC4 or IAP3, is one of the most studied Melanoma; Multiple myeloma; Neuroblastoma; members among the proteins known as Inhibitors of Oral cancer; Osteosarcoma; Ovarian cancer; Apoptosis Proteins (IAPs). This protein family Pancreatic Cancer; Prostate cancer; Thyroid cancer; portrays its main role by preventing apoptotic cell death through direct or indirect inhibition of caspase Identity activity. All members of the IAPs carry at least one BIR domain in their structure, which are generally Other names responsible for caspase interaction. XIAP has three X-Linked Inhibitor of Apoptosis, E3 Ubiquitin BIR domains, enabling interaction with both Protein Ligase, Baculoviral IAP Repeat-Containing initiation and effector caspases. Moreover, it is also Protein 4, RING-Type E3 Ubiquitin Transferase structured with a RING finger domain, which XIAP, E3 Ubiquitin-Protein Ligase XIAP, Inhibitor functions as a ubiquitin ligase (E3), and one UBA of Apoptosis Protein 3, IAP-Like Protein 1, IAP- domain, for binding to ubiquitin, further rendering Like Protein, X-Linked IAP, hIAP-3, hIAP3, XIAP a central role in the ubiquitination process and, BIRC4, IAP-3, API3, ILP1, MIHA, XLP2 thus, implicating such IAP in multiple signaling HGNC (Hugo): XIAP pathways, including cell death, autophagy, immunity, inflammation, cell cycle, and cell Location: Xq25 migration. XIAP overexpression is found in a variety of cancer types and is frequently associated with DNA/RNA chemoresistance and increased risk of relapse. Furthermore, there are many evidences that XIAP Description inhibition may sensitize tumor cells to chemotherapy The entire XIAP gene is approximately 54.2 Kb agents, which make this protein a potential target in (start: 123859724 bp; end: 123913979 bp; cancer. orientation: plus strand). Keywords There are two transcript variants deposited in the XIAP; Interact with caspases; Apoptosis; Bladder NCBI database cancer; Brain cancer; Breast cancer; Cervical (https://www.ncbi.nlm.nih.gov/gene). carcinoma; Colorectal cancer; Esophageal cancer;

Atlas Genet Cytogenet Oncol Haematol. 2020; 24(11) 424 XIAP (X-linked inhibitor of apoptosis) Reis Silva CSM et al.

Figure 1. XIAP protein structure. XIAP (also known as BIRC4 or IAP3) presents two transcripts variants deposited in NCBI database. The protein structure presents 497 amino acids (aa) and is composed of three BIR domain being one of them that responsible for its anti-apoptotic activity, one RING zinc finger domain and an UBA domain. The XIAP structure containing their domains and the specific interactions of each domain, signaling the importance of XIAP in apoptotic pathways through interaction with caspases. The aa positions are indicated.

The transcript variant 1 is the longest transcript CASP7 (caspases-3 and -7) (Suzuki et al., 2001). (cDNA: 8460 bp), while transcript variant 2 differs BIR3 domain is responsible for inhibiting CASP9 in the 5' UTR, compared to transcript variant 1 (caspase-9), thus, preventing the intrinsic apoptosis (cDNA: 8427 bp); however, both transcripts encode pathway (Lukacs et al., 2013). By contrast, diablo the same protein (497 aa). There are nine additional IAP-binding mitochondrial protein binds to both transcript variants reported in Ensembl BIR2 and BIR3 domains, thus inhibiting their (http://www.ensembl.org/): a transcript variant function, increasing the activation of CASP3, containing 8415 bp, which generates a protein of 497 CASP7 and CASP9 (caspases-3, -7 and -9), and aa; a transcript variant containing 528 bp, which promoting apoptosis (Suzuki et al., 2001, Obexer generates a protein of 156 aa; a transcript variant and Ausserlechner, 2014). containing 390 bp, which generates a protein of 16 At its C-terminus region, XIAP carries a RING zinc aa; and six long non-coding RNA-related transcripts finger domain. Although a BIR domain occurs that do not generate proteins (764, 628, 598, 533, 495 among all IAPs, the RING domain, in turn, is found and 157 bp). only in XIAP, BIRC2 and BIRC3. For XIAP, the RING domain involves an E3 ligase effect, Protein indicating an important activity on protein ubiquitin process (Nakatani et al., 2013). Additionally, the Description RING domain was shown to be involved in NFKB1 X-linked inhibitor of apoptosis (XIAP), also referred signaling and MYC proto-oncogene stability, to as BIRC4, belongs to a family of proteins known contributing to cancer progression (Jiang et al., as Inhibitors of Apoptosis Proteins (IAPs). This 2019), and also on the migratory and invasive protein family is recognized, mainly, for inhibiting potential of cancer cells (Liu et al., 2012). caspase activity, either directly or indirectly, thus preventing apoptotic cell death. Such propriety is Expression generally associated to their distinctive BIR Vischioni and colleagues (2006) assessed XIAP (baculovirus IAP repeat) domain, a conserved expression in a variety of normal adult human tissues sequence of nearly 80 amino acids with a centered in an extensive study using immunohistochemistry, Zn+2, which may occur in numbers of one or three where it displayed an heterogenous pattern. Higher among members of this family. In fact, eight human intensity immunoreactivity was mainly observed in IAPs have been described so far: BIRC1 ( NAIP), the small intestine (specifically in Paneth cells and BIRC2 (cIAP1), BIRC3 (cIAP2), BIRC4 (XIAP), absorptive epithelium) and in epidermal BIRC5 (Survivin), BIRC6 (Bruce), BIRC7 (Livin) keratinocytes within all the layers of the skin (except and BIRC8 (ILP-2) (Silke and Vucic, 2014). in stratum corneum). XIAP also displayed XIAP presents three BIR domains located at the N- considerable immunoreactivity in specific areas of terminus region as demonstrated in Figure 1. Despite the stomach, large intestine, thymus, testicles, ovary similarities shared among BIR domains, their and mammary gland. It has been found in a gradient functions may vary according to the IAP member. within tissues such as squamous epithelia and in BIR1 interacts with proteins that modulate NFKB1 more differentiated cells in other tissues like (NFκB) signaling (Lu et al., 2007). BIR2 and the esophageal epithelium (Vischioni et al., 2006). linker region between BIR1 and BIR2 domain are necessary for inhibition of effector CASP3 and

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Indeed, the expression of XIAP is not limited to cell et al., 2005; Evans et al., 2018). XIAP protein but not types that are constantly undergoing apoptosis or its mRNA was found to be highly increased in tissues with faster cell turnover. childhood acute lymphoblastic leukemia compared Given that the main function of XIAP is to impair to control bone marrow mononuclear cells, and no both intrinsic and extrinsic apoptosis pathways, this correlation between protein levels and mRNA was finding is of particular interest in oncology research, seen either, indicating post-transcriptional regulation as mechanisms to avoid cell death are one of the (Hundsdoerfer et al., 2010). XIAP expression may main factors that contribute to the formation of solid also be regulated by an alternative translation tumor masses. Not coincidentally, upregulating initiation by a 162-nucleotide internal ribosome XIAP expression is one of the means by which tumor entry site (IRES) located in the 5' untranslated region cells may accomplish such resistance. Therefore, of XIAP mRNA (Holcik et al., 1999; Holcik XIAP expression levels may directly determine the Korneluk, 2000). sensitivity of tumor cells to apoptosis (Eckelman et In addition, different expression levels in normal al., 2006; Yang et al., 2018). cells of the same lineage in different organs indicates XIAP was found to be overexpressed in a variety of that IAP expression is also influenced by cell type cancer types and is frequently associated with and organ-dependent regulatory mechanisms chemoresistance and increased risk of recurrence, (Vischioni et al., 2006). Moreover, Yan and being, generally, a predictive marker of poor colleagues (2004) demonstrated a tumor stage- prognosis of the disease (Srinivasula & Ashwell., dependent increase of both XIAP mRNA and protein 2008; Obexer Ausserlechner, 2014). In this matter, expression in renal cell carcinoma (Yan et al., 2004). Gao and colleagues (2019) conducted a systematic At a protein level, XIAP activity may also be review and metanalysis to determine the prognostic negatively regulated by the interaction with specific value of XIAP in patients with different tumor types. endogenous inhibitors, i.e. DIABLO (diablo IAP- The analysis included 40 articles and more than binding mitochondrial protein), HTRA2 and XAF1 6,500 patients and concluded that the majority of the (XIAP-associated factor-1) (Srinivasula & Ashwell., studies correlated high XIAP expression levels to an 2008; Desplanques et al., 2009; Ye et al., 2019; unfavorable prognostic factor for clinical outcomes Abbas & Larisch, 2020), or stabilized by other IAPs in cancer patients (Gao et al., 2019). However, some and proteins to enhance its activity (Dohi et al., 2004; discrepancies have been noted, as higher XIAP Rajalingam et al., 2006). XIAP also forms a complex levels was also correlated to longer overall survival with SIVA1 and NR2C2 (TAK1), which inhibits in non-small cell lung cancer patients (Ferreira et al., XIAP/TAK1/ TAB1 -mediated NFκB activation, 2001b). Additionally, XIAP expression did not show activates JNK activity and modulates apoptosis any prognostic significance in cervical carcinoma responses (Resch et al., 2009). (Liu et al., 2001) nor was that able to predict the response to chemotherapy in patients with advanced Localisation NSCLC (Ferreira et al., 2001a) . Subcellular localization of XIAP is heterogenous, An extensive study was conducted by Hussain and but it is predominantly cytoplasmic, being found in colleagues (2017) to assess the expression of XIAP the nucleus also in the membrane. in over 1000 Middle Eastern breast cancer cases by Immunofluorescence of transfected HeLa cells immunohistochemistry, and found this IAP to be indicated that XIAP localized to the cytoplasm, overexpressed in 29.5% of the cases with an being more prominent in the peri-nuclear region. The association to tumor size, extra nodal extension, study also aimed to evaluate if co-expression of triple negative breast cancer and poorly XIAP and XAF1 could alter its localization and differentiated breast cancer subtype (Hussain et al., concluded that the expression of XAF1 induced 2017). Expression and clinical significance of XIAP redistribution of XIAP from cytoplasm to nucleus in a wide variety of cancer was further assessed and (Liston et al., 2001). demonstrated in ovarian, lung, colorectal, thyroid, Germ and Sertoli cells displayed XIAP in both prostate, cervical, melanoma, salivary gland, cytoplasm and nucleoli (Vischioni et al., 2006). pancreatic, cervical cancers, kidney, liver, Fluorescence staining of hNOKs (human normal oral neuroblastoma, oral, among others. Some of these keratinocytes) revealed XIAP to be localized mainly will be further discussed herein. in the cytoplasm and perinuclear areas, whereas in XIAP expression was shown to be regulated at Tca8113 cell line (squamous cell carcinoma of the multiple levels, including transcriptional, post- human tongue) high levels of this IAP were found transcriptional and translationally regulation. both in the cytoplasm and the nucleus (Gao et al., Transcriptional activation of XIAP may be 2006). In gastric cancer tissue samples, XIAP controlled via NFkB pathway and ATP7A (ATPase expression was detected exclusively in the copper transporting alpha) (Karin & Lin, 2002; Dai cytoplasm (Dizdar et al., 2017).

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Figure 2. XIAP (BIRC4) is a multi functional protein. XIAP is involved in multiple cellular signaling pathways and cellular processes, including cell death, inflammation, cell cycle, and cell migration. The multifunctionality of XIAP is possible due to the different domains presented. The main function attributed to XIAP is its antiapoptotic activity, acting on intrinsic and extrinsic apoptotic pathways. XIAP binds and inhibits CASP9 (caspase 9) and its effectors CASP3 and CASP7 (caspase 3 and caspase 7). XIAP also acts on caspase inhibition by ubiquitination. XIAP has also a role in the suppression of autophagy, once its depletion resulted in increased expression of SQSTM1 (p62), a feature induced, in fact, by prevention of the ubiquitin- proteasomal degradation of SQSTM1 mediated by E3 ligase activity of XIAP. XIAP has been linked to cytochrome C release, suggesting that XIAP may enhance mitochondrial membrane permeabilization. It was demonstrated that XIAP physically interacts with HSP70 and, interestingly, that the use of HSP70 inhibitors promotes down-regulation of XIAP. In addition, XIAP regulates TAB1/NR2C2/NFKB1 axis modulating apoptosis.

XIAP displayed different patterns of localization in CASP9 (caspase-9), and the effector CASP3 and pancreas: acinar exocrine cells showed stronger CASP7 (caspases 3 and 7), via its BIR3 and BIR2 staining in a granular supranuclear position (alike in domains, respectively, as demonstrated in figure 2 glands of the small intestine and in the bronchial (Obexer and Ausserlechner, 2014) epithelium); while ductal cells presented XIAP Another important mechanism for caspase inhibition diffused in the cytoplasm (Vischioni et al., 2006). A by XIAP involves the E3 ligase activity of the RING granular pattern in the cytoplasm had already been domain, which is correlated with ubiquitination of described in NSCLC cells, mainly in XIAP-bound caspases. Thus, it can be concluded adenocarcinoma sections (Ferreira et al., 2001a; that XIAP interferes with extrinsic as well as Ferreira et al., 2001b). intrinsic death pathways (Pistritto et al., 2016). Such XIAP membrane localization was described in ubiquitination activity may be associated with XIAP endometrial glands, more prominently in brush itself, XIAP-interacting proteins involved in border or basolateral type. The interaction of XIAP apoptosis, and other different targets involved in with bone morphogenetic protein (BMP) type I apoptosis (Galban and Duckett, 2010). XIAP has receptors via its RING-finger domain also suggests also been correlated to suppression of autophagy, a possible localization in the plasma membrane once depletion of this IAP resulted in increased (Yamaguchi et al., 1999; Vischioni et al., 2006). expression of SQSTM1 (p62), a feature induced, in fact, by prevention of the ubiquitin-proteasomal Function degradation of SQSTM1 mediated by E3 ligase XIAP function has been widely described, activity of XIAP (Huang et al., 2019). presenting involvement in multiple cellular signaling Another study evidenced that XIAP also localizes to pathways, including cell death, immunity, the mitochondria, deregulating its functions, inflammation, cell cycle, and cell migration (Vucic, especially concerning cytochrome c release, 2018). This multiplicity of activities is partially due suggesting that XIAP may enhance mitochondrial to the distinct domains present in XIAP. Still, the membrane permeabilization and control cytochrome main function of this protein is the inhibition of the c release (Chaudhary et al., 2016). Furthermore, the apoptosis cascade due to its binding to the initiator tumor suppressor protein SEPTIN4, expressed in the

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outer mitochondrial membrane, promotes cell death mutations, amplifications, deep deletions and through the antagonism of XIAP, leading XIAP to multiple alterations were considered, the total of execute ubiquitination and degradation of BCL2 cancer samples bearing any type of genetic alteration and, consequently, apoptosis (Edison et al., 2017), in XIAP was 351 (0.8%). reinforcing the role the mitochondria plays in XIAP homeostasis. Implicated in Recently, it was demonstrated that XIAP physically interacts with HSP70 and, interestingly, that the use Bladder cancer of HSP70 inhibitors promotes down-regulation of XIAP, BIRC7, and BIRC5 were found to be XIAP in both cancer cell lines and xenograft tumors simultaneously expressed in bladder cancer cells, (Cesa et al., 2017) . with synergistic effects on cell growth and apoptosis. In normal development, XIAP levels and function Knockdown assays targeting these three genes were studied using XIAP-deficient mice. synergistically inhibited the proliferation and in vitro Histopathological analysis revealed no differences transformation ability, while also promoting compared to wild-type mice and, moreover, no apoptosis (Yang et al., 2010). defects in induction of caspase-dependent or - XIAP levels can be considered a biomarker of independent apoptosis were observed. However, malignancy for bladder carcinoma, once it was found other IAPs proteins were found to be upregulated, up-regulated in urine samples from bladder including BIRC2 and BIRC3, which suggests the carcinoma patients compared to samples of patients existence of a compensatory mechanism (Harlin et with non-malignant bladder diseases (Srivastava et al., 2001). Still, in cancer, high XIAP levels have al., 2015). In urinary cancer, XIAP expression was been correlated with a poor prognosis (Cossu et al., shown to play a key role in the maintenance of tumor 2019). phenotype mediating multiple pathways: XIAP overexpression promoted bladder cancer invasion in Homology vitro and lung metastasis in vivo through activation XIAP has high homology among different species of the MAPK1 / NCL/ ARHGDIB axis (Yu et al., (Table 1). 2018). Also, its BIR domain regulated the EGFR % Identity for: Homo translation by suppressing MIR200A expression and Symbol Protein DNA sapiens BIRC7 promoting cancer development and progression vs. P. troglodytes XIAP 98.4 98.9 (Huang et al., 2017). The RING domain of XIAP vs. C. lupus XIAP 87.4 91.1 also contributed to malignant transformation in bladder cancer, once it inhibited the expression of vs. B. taurus XIAP 87.7 91.8 TP63, a known tumor suppressor, critical for the vs. M. musculus Xiap 89.5 90.1 transformation of normal urothelial cells (Jin et al., vs. R. norvegicus Xiap 89.9 89.8 2016). vs. G. gallus XIAP 59.2 66.7 In T24 and 5637 cell lines, XIAP overexpression vs. X. tropicalis xiap 53.0 61.7 was reverted by embelin treatment that promoted a vs. D. rerio xiap 51.1 55.6 dose-dependent cell death mediated by the PI3K/AKT pathway (Fu et al., 2016). The use of vs. A. gambiae AgaP_AGAP012677 43.0 52.1 DIABLO IAP-binding mitochondrial protein Table 1. Comparative identity of human XIAP with other mimetics (UMUC-6, UMUC-12, and UMUC-18) in species (Source: http://www.ncbi.nlm.nih.gov/homologene) combination with typical chemotherapy drugs like cisplatin and gemcitabine promoted increased Mutations apoptosis, decreased microvessel density and Somatic decreased cellular proliferation that was shown to be related to the inhibition of IAPs, including XIAP Recurrent mutations in the XIAP gene are rare. (Lee et al., 2013). Among the 47,186 samples reported in COSMIC (Catalogue of Somatic Mutations in Cancer; Brain cancer http://cancer.sanger.ac.uk/cancergenome/projects/c New potential therapeutic targets in glioblastomas osmic), 182 mutations were reported in XIAP (138 were investigated by analyzing the expression and missense substitutions, 23 synonymous function of eight proteins that are known to play a substitutions, 14 nonsense substitutions, 3 frameshift role in cell survival and therapy resistance. The deletions and 2 frameshift insertions). In cBioPortal analysis of 50 samples from glioblastoma patients by (http://www.cbioportal.org), among the 42,119 (159 immunohistochemistry revealed high expression of studies) cancer samples accessed, only 0.5% XIAP and ABCG2 (also known as BCRP, a member presented XIAP mutations (corresponding to 195 of the ABC transporters that use ATP to efflux mutations, of which 171 are missense substitutions, endogenous small molecules and exogenous 22 truncated genes and 2 other mutation). When cytotoxic drugs) at the protein level were related to

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poor survival (Emery et al., 2017). Another study thus conferring resistance to radio and chemotherapy evaluated the expression of anti and pro-apoptotic in glioblastoma (Yang et al, 2017). genes in 30 samples of glioblastoma patients by real- Breast cancer time PCR, which found higher levels of XIAP and BCL2 in glioblastoma samples compared to 10 IAPs were shown to be overexpressed in various samples from white matter control (Tirapelli et al., numbers of cancers, including breast cancer and 2017). were associated with a poor prognosis and drug Additionally, higher XIAP mRNA levels were found resistance (Moraes et al., 2015, Huang et al., 2018), on CD133+ compared to CD133- adult glioblastoma making them an interesting target for therapy. In primary cultured cells (LIU et al., 2006). Higher immunohistochemical experiments, it was shown levels of XIAP were also seen in DAOY and that XIAP positively stained the majority of breast D283MED cells compared to normal human cancer cells with moderate or strong intensity astrocytes and immortalized fibroblasts. Moreover, (Zohny; Zamzami; El-Shinawi, 2018). expression of XIAP inversely correlated with that of In another study, it was found that in one third of CDKN1A (p21), suggesting IAPs may be involved breast cancer patients presented XIAP in cell cycle control by CDKN1A suppression overexpression, which was associated with a (CHEN et al., 2018). reduced overall survival (Hussain et al., 2017). Treatment with IAP inhibitors LCL161 or LBW242 In a study with inflammatory breast cancer (IBC) alone or in combination with conventional was noticed that XIAP was also overexpressed in chemotherapeutic agents, i.e. vincristine or cisplatin, IBC patient tumors and high-grade breast cancers, as well as RNAi-mediated knockdown of XIAP, corroborating XIAP overexpression in breast cancer arrested the cell cycle at the G2/M phase through (Evans et al., 2018). downregulation of CCNB1 - CDK1 and CCNA2 - Additionally, high XIAP expression was associated CDK1/ CDK2 complexes in DAOY and D283MED with reduced CASP3 activation and apoptosis rates cells (Chen et al., 2018). These IAP inhibitors in breast cancer tumors compared to benign breast combined with chemotherapy also enhanced the lesions. antiproliferative effect on MB cell line through In immunoreactivity studies using breast cancer autophagy induction and CASP3/CASP7-activated samples, high XIAP expression was found, but it did apoptosis (Chen et al., 2016). not correlate with age, tumor size, grade, status of Treatment with IAP inhibitors LCL161 or LBW242 lymph node, expression of ESR1 (estrogen receptor) alone or in combination with conventional and PGR (progesterone receptor). In addition, XIAP chemotherapeutic agents, i.e. vincristine or cisplatin, expression was found in 80% of patients with triple- as well as RNAi-mediated knockdown of XIAP, negative invasive ductal breast cancer and it was arrested the cell cycle at the G2/M phase through related with primary tumor size and reduced disease- downregulation of CCNB1-CDK1 and CCNA2- free survival and overall survival (Zohny; Zamzami; CDK1/CDK2 complexes in DAOY and D283MED El-Shinawi, 2018). cells (Chen et al., 2018). These IAP inhibitors Cervical carcinoma combined with chemotherapy also enhanced the antiproliferative effect on MB cell line through Immunohistochemistry analysis of 15 cases of autophagy induction and CASP3/CASP7-activated normal cervical tissues, 69 cases of cervical apoptosis (Chen et al., 2016). intraepithelial neoplasia (CIN) and 76 cases of In U87MG glioblastoma cells, treatment with cervical carcinoma revealed increased expression of isolinderalactone, a sesquiterpene found in the roots XIAP in tumor than normal tissues, inversely of L. aggregata, resulted in a significant dose- associated with diablo (Smac) expression. In the dependent reduction of XIAP, BIRC5 and BCL2 same study, XIAP expression was associated with levels, and apoptosis induction (Hwang et al., 2019). pelvic lymph node metastasis (Jin et al., 2017). A Crude extracts of medicinal herbs (crude alkaloid semi quantitative RT-PCR analysis of 6 normal and extract of R. stricta and crude flavonoid extract of Z. 41 cancer tissues, including 8 stage I cases, 16 stage officinale) decreased mRNA expression levels of II and 17 stage III revealed no differences in the XIAP, BIRC5 and CCND1, while expression of expression of XIAP between normal and tumor CDNK1A and PMAIP1 were upregulated in samples. However, an unexpected positive U251MG cell line (Elkady et al., 2014). association between low levels of XIAP and disease XIAP and MYC expression were significantly relapse was observed, and an inverse relation decreased in 51A and SU-2 cell lines after treatment between XIAP expression and tumor aggressiveness with HDAC6 inhibitor, resulting in decreased (Espinosa et al., 2006). CHEK1 activity through proteasomal degradation, The crude extract of the Chinese herb Antrodia leading to radio-sensitivity and reduced DNA camphorata induced apoptosis in HeLa and C-33A damage repair capacity of glioma stem cells, a group cells, showing a decrease in the expression of XIAP of 'stem-like' cells hardly to be completely removed, among other anti-apoptotic proteins (Yang et al.,

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2013). Xanthohumol, a prenylated chalcone isolated In HT29 cells, mithramycin A selectively from Humulus lupus, also downregulated expression downregulated XIAP through inhibition of SP1 of anti-apoptotic proteins such as XIAP in Ca Ski binding to its promoter. cervical cancer cell line, inhibiting proliferation Suppression of XIAP transcription, by siRNA, (Yong et al., 2015). enhanced TNFSF10-induced apoptosis even though Colorectal cancer its overexpression significantly attenuated apoptosis induced by MithA plus TNFSF10, indicating a XIAP mRNA expression was shown to be critical role for XIAP in the recovery of TRAIL upregulated in a study comparing 100 cancer to 100 sensitivity in various cancer cells (Lee et al., 2006). normal tissues from patients with sporadic colorectal Impaired CASP3 maturation by XIAP was also cancer by real time PCR, of which half were KRAS identified as one of the underlying mechanisms wild-type and the other half KRAS mutant (Devetzi relating XIAP to TNFSF10 resistance in HCT-116 et al., 2016). XIAP was also shown to be upregulated PIK3CA -mutant cells, as TNFSF10 sensitivity was while pro-apoptotic BAX and BID were efficiently restored after XIAP or proteasome downregulated in HT-29 cells resistant to 5-FU inhibition, indicating that targeting XIAP or the compared to wild type (Manoochehri et al., 2014). In proteasome in cells with PIK3CA mutations, which contrast, the expression of XIAP and other IAPs, are found in 10-20% of colorectal tumors, may except BIRC3, did not show significant differences represent a good therapeutic strategy concerning in the normal mucosa of patients with advanced TNFSF10 (Ehrenschwender et al., 2014). colorectal adenoma (Choi et al., 2017). COLO 205 and HCT-116 cells transfected with The diablo IAP-binding mitochondrial protein shRNA targeting AKAP4 (A-kinase anchor protein mimetic BV6, reduced cellular levels of XIAP, re- 4) resulted in XIAP downregulation among other sensitizing BAX-deficient HCT-116, wildtype HCT- anti-apoptotic molecules, while pro-apoptotic 116, HCT-8 and DLD1 cells grown under hypoxic molecules were upregulated (Jagadish et al., 2015). conditions to TNFSF10 and/or FASLG (CD95L) - TGFB1 / PRKACB (PKA) / PP2A signaling induced cell death (Knoll et al., 2016). In addition, deactivated AKT phosphorylation leading to XIAP-deficient HCT-116 cells showed significant downregulation of XIAP and BIRC5 in FET cell line less TRAIL resistance under hypoxia compared to (Chowdhury et al., 2011 A; Chowdhury et al., 2011 HCT-116 wild type cells (Knoll et a., 2016). BV6 B). also substantially increased 3D radiation response of Bufalin, a steroid-related molecule, in association HCT-15, HT-29 and SW480 cells upon BIRC2 and with 5-fluorouracil reduced the expression of XIAP XIAP degradation, resulting in enhanced irradiation- and other IAPs, while elevated the expression of pro- induced apoptosis and DNA double-strand break apoptotic proteins (Dai et al., 2018). repair hampering (Hehlgans et al., 2015). Agreeing Moreover, MK-2206, an allosteric kinase inhibitor with this, combinatorial treatments with TNFSF10 of AKT, dephosphorylated EZR (ezrin) at the T567 and Smac mimetics or XIAP-targeting drugs were site and led to disruption of AKT-EZR-XIAP cell reported to overcome hypoxia-induced TNFSF10 survival signaling (Agarwal et al., 2014). resistance, demonstrating that a reasonable Phosphorylation of EZR at the T567 site was alternative was to target XIAP as well as TNFSF10 regulated by the IGF1R signaling pathway, and such in order to obtain stronger responses (Knoll et al., activation enhanced cell survival in colorectal cancer 2016). cells by modulating XIAP and BIRC5 in both Upregulation of XIAP might also be responsible for orthotopically implanted GEO tumors, as well as, the acquired resistance to oxaliplatin, as established human patient specimens (Leiphrakpam et al., oxaliplatin-resistant SW480 and HT29 cells were 2014). shown to express significantly higher levels of XIAP SATB2 (special AT-rich binding protein-2) and lower levels of MIR122 compared to wild types. overexpression resulted in upregulation of XIAP and A recovery of miR-122 expression was able to CCND1 in CRL-1831 cells (Yu et al., 2017). sensitize these colorectal cancer cells to oxaliplatin- Silencing PIK3CA (PI3K p110α), by siRNA, also mediated apoptosis through inhibition of XIAP resulted in alterations in the expression of XIAP in expression. Thus, XIAP may offer a good strategy KRAS/PIK3CA-mutant HCT-116 (Fernandes et al., for reducing oxaliplatin resistance in colorectal 2016). cancer (Hua et al., 2018). Placet et al. (2018) suggested that P2RY6 receptor Transcriptomic analysis revealed that could be targeted to block XIAP activity in propionibacterial supernatant or its metabolites colorectal cancer. P2RY6 stimulation with its (propionate and acetate) increased pro-apoptotic selective agonist MRS2693 induced XIAP gene expression (TNFSF10) and reduced anti- phosphorylation on Ser87 residue, concomitant to apoptotic gene expression of CFLAR and XIAP phosphorylation of AKT Thr3008 residue, and it was when administered in combination with TNFSF10 in correlated to XIAP increase and maintenance over HT-29 cells (Cousin et al., 2016). time. These findings suggested that P2Y6R

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antagonists could be used to block XIAP activity and expression was strongly related to advanced stage. In enhance the therapeutic effect of drugs such as 5- the same study, high expression of XIAP was also fluorouracil (Placet et al., 2018). related to decreased patient survival rates, indicating Esophageal cancer this as an independent prognostic factor for poor survival outcomes (Kim et al., 2011). Another study Immunohistochemistry analysis of 120 esophageal considering 144 patients also found that XIAP squamous cell carcinoma (ESCC) and 90 esophageal expression levels were significantly related to tumor adenocarcinoma (EAC) tissues with their size, serosal invasion and lymph node metastasis. corresponding normal mucosa samples revealed The authors further demonstrated that XIAP high expression levels of XIAP in tumor tissues. The expression was significantly elevated in HGC-27 same study identified XIAP as an independent and MGC803 gastric cancer cell lines compared to negative prognostic marker in ESCC (Dizdar et al., GES-1 normal gastric epithelial cells (Li et al., 2018). Another study using immunohistochemistry 2018). In addition, among other eight proteins, XIAP of 78 ESCC patients treated with radiotherapy after was seen to be upregulated in AFP (alpha- surgery revealed increased XIAP expression and it fetoprotein) producing gastric adenocarcinoma, and was correlated with tumor differentiation and TNM its overexpression was correlated to poor relapse- stage (Zhou et al., 2013). Schiffmann and colleagues free survival and overall survival, but not in the AFP also reported XIAP expression might serve as a tool non-producing patients (He et al., 2016). to improve outcome prediction and identify high-risk XIAP and BIRC5 levels were evaluated in 201 patients, whom may be a candidate for a more patients who underwent total or subtotal gastrectomy aggressive therapy strategy (Schiffmann et al., and extended (D2) lymphadenectomy. High levels of 2019). Additionally, 170 ESCC patients and 191 both IAPs were seen in gastric cancer tissue healthy people were genotyped and related specimens when compared with normal mucosa and polymorphisms rs8371 and rs9856 with were correlated with an intestinal-type and well- susceptibility to ESCC, and rs8371 polymorphism differentiated gastric cancer, as also to low UICC might serve as an indicator improved clinical stages. High levels of XIAP was detected in lymph efficacy and prognosis (Peng et al., 2017) . node metastasis compared to corresponding primary Treatment of five ESCC cell lines with TNF tumors, which supports the hypothesis that it also combined to cycloheximide (CHX) induced plays an important role in metastatic tumors. XIAP significant apoptosis and decreased expression of overexpression was identified as an independent XIAP and BIRC2. This effect was not seen when negative prognostic marker in diffuse and mixed cells were treated with either TNF or CHX alone, but type of gastric cancer. Tissue microarray revealed XIAP or BIRC2 siRNA transfected cells underwent XIAP was present only in the cytoplasm, whereas apoptosis when TNF was administered alone, a BIRC5 was found in both the nucleus and the result that was further increased by double cytoplasm. The authors also identified a positive knockdown, suggesting XIAP along with BIRC2 correlation between cytoplasmic BIRC5 and XIAP might play an essential role in apoptosis-resistance expression (Dizdar et al., 2017). of ESCC cells (Hikami et al., 2017). XIAP was downregulated after treatment with Esophageal cancer cells treated with siRNA cycloheximide (CHX) and the effect was enhanced targeting XIAP in combination to radiotherapy when combined CHX to TNF, resulting in induced presented decreased cell survival rate and colony apoptosis that may occur by accelerated proteasome- forming efficiency. Besides, nude mice treated with mediated degradation of XIAP and other IAP family siRNA had a decrease in tumor weight and volume members in addition to inhibition of NFKB1- compared to control group, indicating that XIAP dependent synthesis of anti-apoptotic molecules gene silencing could be an allied in radiotherapy (Kitagawa et al., 2015). strategies for esophageal cancer (Wen et al., 2017). Treatment with L-asparaginase in human gastric Treatment with siRNA targeting XAIP also adenocarcinoma cells (AGS) significantly down- enhanced chemosensitivity of ESCC cells, as seen in regulated anti-apoptotic genes i.e. XIAP, BID, a study that combined this strategy with paclitaxel, MCL1, and death receptors TNF and TRADD, while cisplatin, 5-fluorouracil and etoposide (Zhang et al., pro-apoptosis genes i.e. BAK1, BAX, BIK, APAF1, 2007). CASP3, CASP7, and CASP9 were upregulated. Gastric cancer Further analysis confirmed intrinsic apoptosis pathway activation (Sindhu et al., 2018). Treatment An analysis for expression of IAPs in over 1,100 with H72, a synthetic brominated chalcone surgically resected gastric cancer (GC) tissue derivative, reduced protein levels of XIAP, specimens revealed XIAP was present in 20% of the BCL2L1, and BIRC5, while increased levels of cases, whereas XIAP inhibitors, such as XAF1 and BCL2L11 BIM, TNFRSF10A (DR4), and diablo IAP-binding mitochondrial protein, were seen TNFRSF10B (DR5), with no changes in BAX levels in 76.6% and 13.9% of cases respectively. XIAP in MGC803 cells (Zhang et al., 2016).

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Furthermore, scutellarein, a flavone glycoside Kidney cancer obtained by hydrolysis of scutellarin found in herbs XIAP expression was upregulated and associated from Scutellaria genus, induced apoptosis and with poor prognosis in kidney cancer patients inhibited cell proliferation via down regulation of (Mizutani et al., 2007; Bilimet al., 2008). It was also MDM2, which activates the tumor suppressor shown that the decrease in the expression of XIAP protein TP53, leading to down regulation of XIAP, by antisense oligonucleotide enhanced sensibility of BIRC2 and BIRC3 in a dose-dependent manner in renal cell carcinoma cells to FAS/ TNFSF10- AGS and SNU-484 gastric cancer cells (Gowda mediated cytotoxicity (MizutaniI et al., 2007). In Saralamma et al., 2017). CDK7 selective inhibition renal cell carcinoma, XIAP expression increased by BS-181, a pyrimidine-derived compound, from early (pT1) to advanced tumor stages (pT3), induced apoptosis due to a significant decrease in similarly to dedifferentiation stages and tumor XIAP and CCND1 expression in BGC823 cells aggressiveness (Yan et al., 2004; Ramp et al., 2004). (Wang et al., 2016). Among the different histological renal cell A double knockdown of both XIAP and BIRC5 carcinomas, it was observed that the clear cell type, expression by siRNA resulted in a notable increase that has a poor diagnosis, had a higher XIAP in apoptosis rates and suppression of cell expression than the papillary (Yan et al., 2004). In proliferation compared to cells submitted to a single addition, XIAP expression was found in 137 of 145 knockdown of either BIRC5 or XIAP (Li et al., (95%) of the investigated clear cell renal cell 2018). carcinoma, a tumor of the kidney that accounts 70% XIAP levels were inversely correlated to expression of all renal cell carcinoma. of MIR509-3p in tissue specimens collected from patients with gastric cancer, which was a clinically Leukemia significant miRNA detected in higher abundancy in Leukemia cells appear to have anti-apoptotic patients with favorable survival states, both in The proteins in order to survive under hostile conditions Cancer Genome Atlas and in an independent cohort (Walsby et al., 2013), and studies have shown that (Pan et al., 2016). Paired tissues revealed significant these molecules may be useful as prognostic markers downregulation of miR-509-3p in tumor tissues, and (Tamm, 2004). XIAP was frequently overexpressed such downregulation was strongly correlated to poor in leukemia cells, serving as regulators in the cell outcomes (Sun et al., 2017). survival (Hu et al., 2014). Head and neck squamous cell In a panel made purposely for the study of the carcinoma relation of IAPs and leukemia containing 60 human tumor cell lines showed, among acute myeloid Immunohistochemistry assays revealed XIAP leukemia (AML) blasts derived from newly expression in 40 of out 59 sections from routinely diagnosed patients, that patients with low levels of processed specimens of head and neck squamous XIAP had a longer survival rate and were inclined to cell carcinoma (HNSCC), in which staining varied a longer median remission duration. This finding from weak or focal to strong or diffuse (Nagi et al., implied that XIAP has a potential prognostic value 2007). in AML (Tamm et al., 2000). In adult acute myeloid XIAP expression was found in 17 out of 60 samples leukemia (AML), XIAP expression was lower in accessed, which was associated with cisplatin AML cells with granulocytic differentiation when resistance and poor clinical outcome in advanced compared to myelomonocytic-differentiated cells, HNSCC patients. Chemotherapy with cisplatin which suggests that XIAP plays a role in normal induced XIAP expression. In HNSCC cells, cisplatin monocytic and malignant differentiation. Supporting sensibility was significantly increased after this finding, downregulation of XIAP blocks inhibition of XIAP by siRNA. Along with alcohol monocytic differentiation induced by bryostatin 1 in consumption and lymph node metastasis, XIAP was leukemia cells (Tamm, 2004). found to be an independent prognostic marker of One of the most well-known XIAP inhibitor is advanced HNSCC patients (Yang et al., 2012). embelin, a cell-permeable and small molecule that Moreover, Yang and other colleagues (2018) inhibits XIAP through DIABLO IAP-binding reported that patients with HNSCC co-expressing mitochondrial protein. Embelin was shown to high levels of XIAP and BIRC2 had shorter overall promote downregulation of XIAP and release of and disease-free survival compared to patients CASP9, which normally initiates caspase cascades expressing low levels of both IAPs, indicating a and leads to apoptosis. Furthermore, embelin synergistic effect of these proteins on prognosis induces apoptosis in leukemia cell line HL60 by (Yang et al., 2018). XIAP downregulation (Hu et al., 2014). Depletion of XIAP, by shRNA, significantly Additionally, it was demonstrated that low-toxicity enhanced cell death after treatment with TNFSF10 embelin sensitization of HL60 cells to TNFSF10 - combined to bortezomib in UPCI:SCC089 and induced apoptosis was not intimately related to UPCI:SCC090 cell lines (Bullenkamp et al., 2014).

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XIAP inhibition, showing that low-toxicity embelin natural extract derived from Artemisia capillaris alone or jointly with TNFSF10 did not change the obtained in ethyl acetate displayed growth and expression of XIAP (Hu et al., 2014). There are other proliferation inhibition, induced apoptosis, increased molecules proposed as XIAP inhibitors, including levels of cleaved caspase-3 and decreased XIAP, CDKI-73, which also inhibited MCL1, BCL2, BIRC5, and MCL1 expression in HepG2 and Huh7 CCND1 and CCND2 (Walsby et al., 2013), and cell lines (Yan et al., 2018). nilotinib, which was shown to inhibit the expression Lung cancer of XIAP in two MDM2-overexpressing cell lines, suggesting that nilotinib-mediated XIAP inhibition In a study of the protein signature for non-small cell was dependent of MDM2, since this was not lung cancer (NSCLC) prognosis, XIAP was observed for MDM2-negative cell line (Zhang et al., differentially expressed between NSCLC and benign 2014). In leukemia cells, the co-treatment with lung tumor, indicating that XIAP is a potential SAHA and S116836 repressed anti-apoptotic biomarker for malignancy in lung tumors. Along proteins, including XIAP (Bu et al., 2014). with other proteins, XIAP was also correlated to Natural products were also studied regarding its invasion and lymph node metastasis, as well as effects on XIAP inhibition, for instance, AVO (an squamous differentiation (Liu et al., 2014). In essential oil from Artemisia vulgaris L) decreased agreement, Huang and coworkers (2015), reported the expression of XIAP leading to inhibition of the high levels of XIAP in lung cancer tissues compared activation of caspases 9 and 3 in HL60 leukemia to adjacent tissues samples (Huang et al., 2015). cells (Saleh et al., 2014). In contrast, Moravcikova et al. (2014) indicated that XIAP was not an effective suppressor of the Liver cancer apoptosome apparatus activity in NSCLC cells, In hepatocellular carcinoma patients, XIAP suggesting that apoptosome-generated caspase-3 expression was associated with poor overall survival activity can overcome the potential caspase and, in cell lines, was shown to play an important inhibitory effect of XIAP. role in modulating cell apoptosis and cell cycle Baykara and colleagues (2013) also investigated the progression through regulation of CDK4, CDK6 and relation of XIAP with clinical parameters in NSCLC. CCND1 via NFKB1 and PTEN pathways (Che et al., XIAP levels were determined by ELISA in samples 2012). Treatment of hepatocellular carcinoma cells from 34 NSCLC patients and 44 healthy individuals, with embelin resulted in increased apoptosis and but no correlation between serum XIAP levels and decreased cell proliferation via an arrest at the G1 response to chemotherapy, progression free-survival phase (Che et al., 2012). In contrast, it was observed or overall survival were found (Baykara et al., 2013). that apoptosis resistance may be related to a Kang and colleagues (2008) performed an evaluation significantly lower expression of XAF1, but not of the association between XIAP polymorphisms XIAP in poorly differentiated hepatocellular and the risk for lung cancer. The authors identified carcinoma tissues (Sakemi et al., 2007). Zhu and 12 SNPs and selected 4 of them for large-scale colleagues reported lower levels of XAF1 expression genotyping based on their frequencies and haplotype in SMMC-7721, HepG2 and BEL-7404 cell lines, as tagging status, but no evidence of relation of XIAP well as in liver cancer tissues compared to their polymorphisms with the risk of lung cancer was paired non-cancer hepatic tissues. Adenovirus- observed (Kang et al., 2008). mediated XAF1 expression (Ad5/F35-XAF1) XIAP-mediated ERK activation upregulated NCL significantly inhibited cell proliferation and induced (nucleolin) expression, which was able to stabilize apoptosis, while significantly suppressed xenograft ARHGDIB mRNA and mediate lung metastatic (Yu tumor growth of hepatocarcinoma cells (Zhu et al., et al., 2018). In lung cancer cells, XIAP inhibited 2014). mature SMAC-induced apoptosis by degrading it XIAP was also associated with therapeutic resistance through ubiquitination (Qin et al., 2016). to the histone deacetylase (HDAC) inhibitor JNJ- Combined treatment of lambetianic acid (LA) and 2648158, which induced the transcription of XIAP TRAIL displayed significantly decreased through AP1 expression activation, conferring antiapoptotic proteins such as XIAP, while also resistance to apoptosis (Wang et al., 2018). disrupting its binding with CASP3 or NFKB1, Moreover, Winkler and colleagues (2014) reported enhancing TNFSF10-induced apoptosis (Ahn et al., XIAP to play an important role in the pro-survival 2018). function of the exportin cellular apoptosis Lymphoma susceptibility (CAS) in hepatocellular carcinoma models (Winkler et al., 2014). Mantle cell lymphoma, a poor prognosis and Cisplatin treatment downregulated XIAP metastatic-related non-Hodgkin B-cell malignancy, expression, while XIAP knockdown by siRNA presented overexpression of IAPs, including XIAP. enhanced the pro-apoptotic effects of cisplatin in In mantle lymphoma cells, B-PAC-1, a procaspase LM3 cell line (Shang et al., 2018). A fraction of the activating compound, induced apoptosis by the

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sequester of Zn bound to procaspase- 3, (Sarkar et Multiple myeloma al., 2015) or when analyzing the anti-tumor Multiple myeloma cells exhibited high levels of properties of puerarin (Gan Yin, 2014). XIAP protein, which was associated with myeloma- Similar to findings in mantle cell lymphoma, XIAP related growth factors. In the same study, XIAP protein was upregulated in other lymphomas, such as silencing by RNAi increased drug sensitivity in in Burkitt's lymphoma, a highly aggressive type of non- vitro assays and reduced in vivo tumor formation. Hodgkin B-cell lymphoma (Aaqarni et al., 2018). In Multiple myeloma cells also expressed XAF1, which lymphoma cells, antitumor properties of indole-3- antagonizes the caspase inhibitor function of XIAP carbinol was related to XIAP downregulation (Desplanques et al., 2009). (Perez-Chacon; Rios; Zapata, 2014). In B-cell lymphomas, XIAP was overexpressed and Neuroblastoma associated with chemoresistance and shorter survival In neuroblastoma patients, XIAP was found in 18 outcomes. Double knockdown of XIAP and USP9X among the 19 cases analyzed, and the level of XIAP delayed lymphoma development, corroborating was higher within patients that had no bone marrow XIAP as a target in lymphoma (Engel et al., 2016). metastasis. XIAP expression was also higher in Medulloblastoma patients with favorable histology regardless of bone marrow status. XIAP expression had no significant XIAP was shown to be upregulated in difference on tumors with undifferentiated/poorly medulloblastoma cells, while XIAP inhibitors differentiated histology compared to differentiating reduced cell proliferation and induced cell death. In subtypes (Osman et al., 2013). Post transcriptional fact, this effect was also seen in the subpopulation and transcriptional mechanisms were related with CD133+ stem-like medulloblastoma cells, for which high XIAP expression, which had been targeted by XIAP expression displayed even higher levels. In diablo IAP-binding mitochondrial protein mimetic agreement, XIAP expression in cytoplasm was LBW242 in neuroblastoma. Using microarray found in 75% of the medulloblastoma tissues analysis, XIAP mRNA was associated with risk of compared with no expression in normal brain tissues relapse in a cohort of 101 neuroblastoma patients (Chen et al., 2016). Inhibition of XIAP, BIRC2 or (Eschenburg et al., 2012). In paired neuroblastoma BIRC3 combined with conventional chemotherapy cell lines obtained from a primary tumor of a female resulted in cell cycle arrest at G2/M phase in patient pre- and post-chemotherapy (CHLA-15 and medulloblastoma cells (Chen et al., 2018). These CHLA-20), XIAP was highly expressed in CHLA- findings indicated that XIAP was a potential 20 cells, which had undergone an intensive treatment diagnostic marker and therapeutic target in with cyclophosphamide, doxorubicin, cisplatin and medulloblastoma. teniposide (Frommann et al., 2018). Melanoma Oral cancer In melanoma, the machinery behind the high Using tissue microarray, high XIAP expression was resistance may be related to overexpression of associated with a significant reduction in overall proteins of the IAP family, including XIAP (Hiscutt survival in a cohort of 193 squamous cell carcinomas et al., 2010; Mohana-Kumaran et al., 2014). XIAP (Frohwitter et al., 2017). HSC-3 cells treated with was associated with cell growth, tumorigenesis, ursodeoxycholic acid (UDCA) and Ca9-22 cells metastasis as well as progression in melanoma cells treated with furano-1,2-naphthoquino (FNQ) and (Li; Ke; Wang, 2012), and it was shown to be PP2 (a Src-specific inhibitor) presented XIAP overexpressed in primary cutaneous and metastatic downregulation (Lin et al., 2014; Pang et al., 2015). melanoma tissues (Hiscutt et al., 2010). In a study where XIAP expression was investigated in 55 Osteosarcoma samples of clinical patients and where samples Qu and colleagues reported that XIAP mRNA and consisted mainly of superficial spreading melanoma, protein levels were increased in osteosarcoma XIAP expression was found to be higher in late stage compared to adjacent non-tumoral tissues in a cohort primary cutaneous melanoma. There was also a of 60 tissues from osteosarcoma patients using significant difference on the percentage of cells quantitative PCR and immunohistochemistry positive for XIAP in sample obtained from patients analysis. The authors also correlated higher that were stage II melanoma and benign nevi. When expression of XIAP to advanced clinical stage, larger analyzing the range of thickness of primary tumors, tumor size and metastasis compared to patients the increase on XIAP expression was associated with expressing lower levels of XIAP. Using MG63 a greater Breslow thickness (Tian; Lee, 2010). In cellular model, a shRNA targeting XIAP efficiently another study, XIAP expression was also higher on decreased cell proliferation and colony formation, thick cutaneous melanoma than when compared to induced apoptosis and cell cycle arrest at G0/G1 thin ones (Emanuel et al., 2008). phase, displayed enhanced chemosensitivity in combination with doxorubicin or cisplatin, and

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inhibited tumor growth in nude mice (Qu et al., MAPK and ATM / CHEK2 (CHK2) pathways, 2015). followed by suppression of the antiapoptotic factors Treatment with an aqueous plus a triterpene extract BCL2L1, BCL2, and XIAP (Li et al., 2016). of Viscum album L. led to strong inhibition of Inhibition of NFKB1 and BIRC6-XIAP complex proliferation and apoptosis, and enhanced sensitivity induced by 10H-3,6-diazaphenothiazine treatment to doxorubicin, etoposide and ifosfamide in 143B reduced metastasis capacity of A2780 cancer cell and Saos-2 cell lines, which were associated with line (Zhang et al., 2017). In SKOV3/DDP cells, downregulation of XIAP, BIRC5 and CLSPN inhibition of NFKB1 and reduced levels of XIAP (Kleinsimon et al., 2017). In addition, the was also observed after treatment with noscapine, a carotenoids fucoxanthin and its metabolite non-toxic benzylisoquinoline alkaloid extracted fucoxanthinol induced apoptosis and cell cycle arrest from opium (Shen et al., 2015). at G1 phase in osteosarcoma human and mouse cell The regulation of XIAP mediated by miRNAs has lines by reducing expression of XIAP, BIRC5, been addressed and multiple miRNAs can regulate BCL2, BCL2L1, CDK4, CDK6, and CCNE1 XIAP via its 3'UTR. For instance, MIR137 (Rokkaku et al., 2013). sensitized ovarian cancer cells to cisplatin-induced apoptosis via XIAP downregulation in SKOV3 cells Ovarian cancer (Li et al., 2017). Similar results were observed for In ovarian cancer models, proteomic analysis MIR155 that mediated cisplatin-induced apoptosis demonstrated that XIAP had a positive coefficient by targeting XIAP (Chen et al., 2016), and for correlation with IC50 values, indicating a role for MIR509-3p that can directly target XIAP via its XIAP in drug resistance (Zervantonakis et al., 2017). 3'UTR in ovarian cancer cells leading to the In agreement, high XIAP levels were inversely inhibition of cell proliferation and increased correlated with carboplatin response and sensitivity to cisplatin-induced apoptosis (Chen et progression-free survival in patients with ovarian al., 2016). In addition, it was demonstrated that cancer (Zhang et al., 2018). It was also reported that MIR146A?5p regulated three important ADPRH, a tumor suppressor gene, was antiapoptotic genes, including XIAP, BCL2L2 and downregulated in 60% of ovarian cancers and BIRC5 via their 3'UTRs. Decreased levels of promoted upregulation of antiapoptotic proteins, MIR146A?5p led to increased IC50 values for including XIAP (Washington et al., 2015). cisplatin in OVCAR3 and SKOV3 cells (Li et al., In ovarian carcinoma cell lines, treatment with 2017). The MIR149 (which also targets XIAP) was phenoxodiol promoted downregulation of XIAP, significantly downregulated in ovarian cancer inhibited autophagy, as evidenced by decreased tissues and cell lines, for which expression was levels of ATG7, ATG12 and BECN1, and increased correlated with patient prognosis and cisplatin cisplatin sensitivity (Miyamoto et al., 2018). chemoresistance (Sun et al., 2018). The Treatment with 10-chlorocanthin-6-one, a cytotoxic downregulation of MIR215 increased cell agent against HO8910PM cell line, induces proliferation, inhibited apoptosis and decreased apoptosis through activation of PARP1 and caspase- sensitivity to chemotherapy drugs in ovarian cancer 3 cleavage, upregulation of BCL2, and cells through the elevated expression of XIAP (Ge et downregulation of XIAP, BIM and BIRC5 (Li et al., al., 2016). 2018). MK-0752, a γ-secretase inhibitor, induced Extracellular matrix components have been cell growth inhibition through downregulation of addressed as one factor involved in chemoresistance XIAP in a dose- and time-dependent manner (Chen in ovarian cells. The collagen COL11A1 was et al., 2016). demonstrated to activate the signaling pathway Natural product butein, a polyphenol widely SRC/PI3K/AKT/NFκB to induce the expression of biosynthesized in plants, promoted downregulation three IAPs, including XIAP, which was correlated to of XIAP, BIRC5, BIRC2, and BIRC3 in ovarian the inhibition of cisplatin-induced apoptosis in cancer cell lines (Yang et al., 2015). Another natural ovarian cancer cells (Rada et al., 2018). product, an extract of Smilax china L. rhizome, Pancreatic Cancer reduced cell proliferation in a dose-dependent manner and induced apoptosis by activation of XIAP was considered one of the most important caspase-3, PARP1 and BAX and by inhibition of factors in chemoresistance of pancreatic carcinoma, NFκB, BCL2, BCL2L1, BIRC2, XIAP and AKT in and its inhibition increased sensitivity to 5- A2780 cells (Hu et al., 2015). Combined treatment fluorouracil (5-FU). In pancreatic carcinoma cell with cisplatin and biothionol enhanced apoptosis line SW1990, XIAP upregulation was observed in through the downregulation of pro-survival factors cells exposed to 5-FU for up to 30 days. Combined (XIAP, BCL2 and BCL2L1) in ovarian cancer cell treatment of 5-FU and gemcitabine greatly increased lines (Ayyagari et al., 2017). Similarly, 1- apoptosis index when XIAP was inhibited (LI et al, phenylpropadienyl phosphine oxide (PHPO) alone 2006). High XIAP expression was also associated or combined with cisplatin inhibited the PI3K/AKT, with poor outcomes in pancreatic carcinoma

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patients, being an independent predictor and patients that express low levels of XIAP. An associated with tumor invasion status and example of this finding is that 50% of patients whose histological grading (LI et al., 2013). tumors were not confined to the organ (n =92) had The treatment with 7-benzylidenenaltrexone maleate tumor recurrence, whereas the 12 patients with (BNTX) combined to TRAIL downregulated XIAP higher levels of XIAP did not experience recurrence. expression, promoting the release of cytochrome c Patients with low grade tumors and low XIAP levels from mitochondria with caspase activation (KIM et experienced recurrence (more than 25%), whereas al., 2017). The authors suggested that the IAP- none of the patients with higher levels of XIAP had mediated resistance of pancreatic cancer cells could recurrence of the tumors. In the PSA follow-up, 94% be overcome by PKCα/AKT pathway inhibition. of patients that presented higher levels of XIAP were A small-molecule IAP antagonist, AT406, recurrence-free, against 58% of patients with lower significantly inhibited cell survival and proliferation XIAP levels (SELIGSON et al., 2007). in Panc-1 and Mia-PaCa-2 cell lines, and in primary XIAP was found to constitutively express on DU145 human pancreatic cancer cells, while displayed no cells, playing an important role on modulating cytotoxicity to pancreatic epithelial cells. Authors chemosensitivity (Amantana et al., 2004), the noted a degradation of IAP family members (such as presence of XIAP was also found on PC3 cells on XIAP and BIRC2), a release of cytochrome c and immunohistochemistry assays showing that XIAP higher activity of CASP3 and CASP9 (JIANG et al., was localized mainly on the perinuclear region of 2016). this cells (Mceleney et al., 2002). Prostate cancer Thyroid cancer The expression of XIAPs in normal human prostate XIAP elevated expression had been associated with (NP), benign prostatic hyperplasia (BPH), prostatic a high degree of invasiveness, being related to lymph intraepithelial neoplasia (PIN) and prostatic node metastasis in papillary thyroid cancer (Gu et al., carcinoma (PC) was evaluated and showed a 20% 2010), and also was associated with old age, expression among NPs, 27.27% in BPHs, 33.33% in extrathyroidal extension, tumor size, nodal high-grade PIN and varying from 17.39 to 39.21% in involvement, tall-cell variant, advanced stage PC. The latter two did not present Gleason variation disease, and significantly poor disease-free survival (Rodriguez-Barriguete et al., 2015). (Hussain et al., 2015). Through immunohistochemical techniques, XIAP XAF1 (XIAP-associated factor-1) antagonizes expression was seen on human prostate tissue XIAP-mediated caspase inhibition. Loss of XAF1 samples, being observed in normal and malignant expression correlates with tumor progression. It has epithelium, basal cells, but not commonly on stromal been suggested that the G allele of rs34195599 of fibromuscular cells. XIAP expression was typically XAF1 may be a risk factor for the diffused in the cytoplasm; however, a discrete clinicopathological features of papillary thyroid supranuclear staining in coarse clusters was carcinoma (Kim et al., 2013). observed. On regions of benign prostatic hyperplasia XIAP expression varied from 48.8% (Hussain et al., (BPH), XIAP showed the lowest expression. XIAP 2015) to 83% in papillary thyroid cancer (Xiao et al., expression in PC was shown to be significantly 2007) and it was of 25% of insular carcinoma only higher when compared to PIN, NP and BPH moderate positive and non-staining in follicular, (Seligson et al., 2007). In a small cohort, it was found medullary, anaplastic carcinomas, oncocytic that higher levels of XIAP was associated with neoplasms (Xiao et al., 2007). In another study XIAP longer relapse-free survival (Krajewska et al., 2003); expression was positive in 75% of patients, whose additionally, in another study, patients with positive expression was significantly associated with the immunostaining for XIAP had a better prognosis, presence of lateral cervical lymph node metastases. which led to questions concerning the pro-tumor role Additionally, XIAP expression was more frequent in of this IAP in prostate cancer (Rodrèguez- BRAFV600E mutated PTCs than in BRAF wild type Berriguette et al., 2015). PTCs (Yim et al., 2014), however no correlation The higher expression of XIAP also predicted the between these two markers were observed (Gu et al., reduced risk of tumor recurrence in dichotomized 2009). and continuous variable in univariate analysis. When In papillary thyroid cancer, XIAP expression was analyzing patients with primary low-grade cancer, associated with phosphorylated AKT, BCL2L1, and none which had a high expression of XIAP displayed Ki67 proteins leading to increase cell proliferation tumor recurrence (n=23). In contrast, patients with and reduced apoptosis rate that was reverted with low levels of XIAP experienced tumor recurrence treatment with embelin (Hussain et al., 2015). (n=89). The same study showed that patients with TPC-1 and BCPAP cell lines silenced for NFKB1 higher grade or non-confined tumors with an and treated with radiation (131I treatment) elevated XIAP expression have a better prognosis, demonstrated a decrease in cell viability mediated by when analyzing the group, when compared to those XIAP and BIRC2 reduction levels and increased is

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CASP3 levels, demonstrating an induction of recurrent solid tumors, such as pancreatic cancer, apoptosis cascade (Chen et al.,2018). The cell line advanced breast cancer, advanced NSCLC and acute TPC-1 treated with HSP90 inhibitor promoted cell myeloid leukemia. Side effects were limiting factors apoptosis and tumor decreased size caused by in the majority of these studies (Tamm, 2006). inhibition of IAP members, such as XIAP, BIRC5, However, a posterior study demonstrated that it is and BIRC2 (Kim et al., 2016). generally well tolerated in combination with In follicular thyroid carcinoma, XIAP expression standard chemotherapy in acute myeloid leukemia was observed in comparison to non-tumoral thyroid (Katragadda et al., 2013). In fact, a phase II clinical tissue. Additionally, XIAP silencing reverted trial conducted with patients with advanced malignant phenotype, causing a decrease in cell hepatocellular carcinoma revealed that treatment proliferation and an increase in cell apoptosis rate with AEG35156 in combination with sorafenib (Werner et al., 2017). yielded positive results, mainly regarding objective In anaplastic thyroid carcinoma, similar results were responses rates (Lee et al., 2016). observed in patients' tissues where XIAP expression Using structure-based drug design, a was significantly elevated in the invasive area of nonpeptidomimetic small-molecule functioning as a anaplastic thyroid carcinoma samples, while XIAP duas antagonist of XIAP and BIRC2, designated AT- expression was negative in either normal thyroid IAP, demonstrated IC50 values in the nM range for follicular epithelial cells or differentiated papillary breast cancer cell lines. Moreover, this compound thyroid carcinoma. Moreover, silencing XIAP in binds to the BIR 3 domain causing disruption of vitro decreased cancer cell proliferation, migration XIAP and CASP9 and increased levels of cleaved and invasion (Liu et al., 2017). PARP1, indicating activation of apoptosis pathway. For anaplastic thyroid carcinoma, it was Additionally, tumor size reduction was demonstrated demonstrated that XIAP repression may be caused in xenograft models (Tamanini et al., 2017). by overexpression of miR-618 (Cheng et al., 2014). Others XIAP inhibitors have been previously In medullary thyroid carcinoma elevated BIRC5 or reported, however such inhibition was not always in XIAP expression was associated with metastatic a direct-manner. This is the case for embelin, a condition. XIAP, as well as BIRC5 levels, were natural product that promotes down-regulation of negatively associated with patient survival (Werner XIAP and was reported to have promising effects in et al., 2016). leukemia (Hu et al., 2014), pancreatic cancer (Mori et al., 2007) and gastric cancer (Wang et al., 2013). To be noted Funding: Fundaçao de Amparo à Pesquisa do Pharmacological advances targeting XIAP in Estado de Sao Paulo (FAPESP) and Coordenaçao de cancer Aperfeiçoamento de Pessoal de Nivel Superior Development of XIAP inhibitors has been explored (CAPES). in the last few years with significant advances. The use of mimetics has gained considerable attention, References especially concerning their pharmacological and Abbas R, Larisch S. Targeting XIAP for Promoting Cancer physiochemical properties. One strategy refers to Cell Death-The Story of ARTS and SMAC. Cells. 2020 Mar employing modifications in amino acids, such as 9;9(3) using non-natural amino acids, replacing some Agarwal E, Chaudhuri A, Leiphrakpam PD, Haferbier KL, residues - e.g. P2 and P3 -, and modifying the C- Brattain MG, Chowdhury S. Akt inhibitor MK-2206 promotes terminal region. These approaches have been anti-tumor activity and cell death by modulation of AIF and Ezrin in colorectal cancer. BMC Cancer. 2014 Mar 1;14:145 carefully reviewed in Jaquith (2014). Another strategy refers to the development of antagonists of Ahn DS, Lee HJ, Hwang J, Han H, Kim B, Shim B, Kim SH. Lambertianic Acid Sensitizes Non-Small Cell Lung Cancers XIAP based on the N-terminus of mature Smac, to TRAIL-Induced Apoptosis via Inhibition of XIAP/NF-κB where a synthetic compound (GDC-0152) revealed and Activation of Caspases and Death Receptor 4. Int J Mol interesting results. This compound binds to the XIAP Sci. 2018 May 16;19(5) BIR3 domain with K(i) values of 28 nM, activating AlQarni S, Al-Sheikh Y, Campbell D, Drotar M, Hannigan A, apoptosis cell death and, consequently, decreasing Boyle S, Herzyk P, Kossenkov A, Armfield K, Jamieson L, viability and inhibiting tumor growth of breast Bailo M, Lieberman PM, Tsimbouri P, Wilson JB. cancer cell lines and xenografted tumors, Lymphomas driven by Epstein-Barr virus nuclear antigen-1 (EBNA1) are dependant upon Mdm2. Oncogene. 2018 respectively (Flygare at al., 2012). Jul;37(29):3998-4012 The use of antisense oligonucleotide to target XIAP has also been proposed. One example is the Amantana A, London CA, Iversen PL, Devi GR. X-linked inhibitor of apoptosis protein inhibition induces apoptosis AEG35156, a second-generation 19-mer antisense and enhances chemotherapy sensitivity in human prostate oligonucleotide, which, in combination with cancer cells. 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combination in a panel of human ovarian cancer cell lines. Dai XY, Zhou BF, Xie YY, Lou J, Li KQ. Bufalin and 5- BMC Cancer. 2017 Jan 13;17(1):49 fluorouracil synergistically induce apoptosis in colorectal cancer cells Oncol Lett 2018 May;15(5):8019-8026 Baykara M, Yaman M, Buyukberber S, Tufan G, Demirci U, Benekli M, Coskun U, Ozet A, Umit Bagriacik E. Clinical and Dai Y, Rahmani M, Dent P, Grant S. Blockade of histone prognostic importance of XIAP and USP8 in advanced deacetylase inhibitor-induced RelA/p65 acetylation and NF- stages of non-small cell lung cancer. J BUON. 2013 Oct- kappaB activation potentiates apoptosis in leukemia cells Dec;18(4):921-7 through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation Bilim V, Yuuki K, Itoi T, Muto A, Kato T, Nagaoka A, Mol Cell Biol 2005 Jul;25(13):5429-44 Motoyama T, Tomita Y. 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Tumor suppressor XIAP and CIAP1 Play Synergistic Effect on Patient's XAF1 induces apoptosis, inhibits angiogenesis and inhibits Prognosis in Head and Neck Cancer Pathol Oncol Res tumor growth in hepatocellular carcinoma Oncotarget 2014 2019 Jul;25(3):1111-1116 Jul 30;5(14):5403-15 Ye T, Yao H, Xu Y, Zhao X, Lu H, Zhang R. Role of Smac, Zohny SF, Zamzami MA, El-Shinawi M. Concomitance of survivin, XIAP, and Omi/HtrA2 proteins in determining the downregulated active caspase-3 and upregulated X- chemotherapeutic response of patients with cervical cancer chromosome linked inhibitor of apoptosis protein as a treated with neoadjuvant chemotherapy Cancer Biomark sensitive diagnostic approach for breast cancer Mol Cell 2019;26(3):249-259 Biochem 2019 May;455(1-2):159-167 Yim JH, Kim WG, Jeon MJ, Han JM, Kim TY, Yoon JH, Hong SJ, Song DE, Gong G, Shong YK, Kim WB. 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