Modulation of Androgen Receptor DNA Binding Activity Through Direct Interaction with the ETS Transcription Factor ERG
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Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development
International Journal of Molecular Sciences Review Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer and Development Charles Ducker * and Peter E. Shaw * Queen’s Medical Centre, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK * Correspondence: [email protected] (C.D.); [email protected] (P.E.S.) Abstract: Genome expansion, whole genome and gene duplication events during metazoan evolution produced an extensive family of ETS genes whose members express transcription factors with a conserved winged helix-turn-helix DNA-binding domain. Unravelling their biological roles has proved challenging with functional redundancy manifest in overlapping expression patterns, a common consensus DNA-binding motif and responsiveness to mitogen-activated protein kinase signalling. Key determinants of the cellular repertoire of ETS proteins are their stability and turnover, controlled largely by the actions of selective E3 ubiquitin ligases and deubiquitinases. Here we discuss the known relationships between ETS proteins and enzymes that determine their ubiquitin status, their integration with other developmental signal transduction pathways and how suppression of ETS protein ubiquitination contributes to the malignant cell phenotype in multiple cancers. Keywords: E3 ligase complex; deubiquitinase; gene fusions; mitogens; phosphorylation; DNA damage 1. Introduction Citation: Ducker, C.; Shaw, P.E. Cell growth, proliferation and differentiation are complex, concerted processes that Ubiquitin-Mediated Control of ETS Transcription Factors: Roles in Cancer rely on careful regulation of gene expression. Control over gene expression is maintained and Development. Int. J. Mol. Sci. through signalling pathways that respond to external cellular stimuli, such as growth 2021, 22, 5119. https://doi.org/ factors, cytokines and chemokines, that invoke expression profiles commensurate with 10.3390/ijms22105119 diverse cellular outcomes. -
Downloaded Uniformly Processed RNA-Seq Datasets from 3,764,506 High-Throughput Sequencing Samples from Skymap in Raw Count Format19
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 28 April 2020 doi:10.20944/preprints202003.0360.v2 TMPRSS2 transcriptional inhibition as a therapeutic strategy for COVID-19 Xinchen Wang, Ph.D.1*, Ryan S. Dhindsa, Ph.D.1,2, Gundula Povysil, M.D., Ph.D.1, Anthony Zoghbi, M.D.1,3,4, Joshua E. Motelow, M.D., Ph.D.1,5, Joseph A. Hostyk, B.Sc.1, Nicholas Nickols, M.D. Ph.D.6,7, Matthew Rettig, M.D.8,9, David B. Goldstein, Ph.D.1,2* 1Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, 2Department of Genetics & Development, Columbia University Irving Medical Center, New York, 3Department of Psychiatry, Columbia University Irving Medical Center, New York 4New York State Psychiatric Institute, New York 5Division of Pediatric Critical Care, Department of Pediatrics, New York-Presbyterian Morgan Stanley Children’s Hospital, Columbia University Irving Medical Center, New York 6Department of Radiation Oncology, University of California, Los Angeles, Los Angeles 7Department of Radiation Oncology, Veteran Affairs Greater Los Angeles Healthcare System, Los Angeles, California 8Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles 9Division of Hematology and Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, Los Angeles, California *To whom correspondence should be addressed: [email protected] (X.W.), [email protected] (D.B.G.) Abstract There is an urgent need to identify effective therapies for COVID-19. The SARS-CoV-2 host factor protease TMPRSS2 is required for viral entry and thus an attractive target for therapeutic intervention. -
CREB3L2-Pparg Fusion Mutation Identifies a Thyroid Signaling Pathway Regulated by Intramembrane Proteolysis
Research Article CREB3L2-PPARg Fusion Mutation Identifies a Thyroid Signaling Pathway Regulated by Intramembrane Proteolysis Weng-Onn Lui,3 Lingchun Zeng,1 Victoria Rehrmann,1 Seema Deshpande,5 Maria Tretiakova,1 Edwin L. Kaplan,2 Ingo Leibiger,3 Barbara Leibiger,3 Ulla Enberg,3 Anders Ho¨o¨g,4 Catharina Larsson,3 and Todd G. Kroll1 Departments of 1Pathology and 2Surgery, University of Chicago Medical Center, Chicago, Illinois; Departments of 3Molecular Medicine and Surgery and 4Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; and 5Department of Pathology, Emory University School of Medicine, Atlanta, Georgia Abstract cancer in patients; and (c) the implementation of effective molecular-targeted chemotherapies that have relatively few side The discovery of gene fusion mutations, particularly in effects. The discovery of fusion mutations is therefore important, leukemia, has consistently identified new cancer pathways particularly in carcinoma, the most common cancer group in and led to molecular diagnostic assays and molecular-targeted which few gene fusions have been identified (1). The recent chemotherapies for cancer patients. Here, we report our discoveries of ERG (2) and ALK (3) gene fusions in prostate and discovery of a novel CREB3L2-PPARg fusion mutation in lung carcinoma, respectively, increase the prospect that new thyroid carcinoma with t(3;7)(p25;q34), showing that a family diagnostic and therapeutic strategies based on gene fusions will of somatic PPARg fusion mutations exist in thyroid cancer. The be applicable to common epithelial cancers. CREB3L2-PPARg fusion encodes a CREB3L2-PPAR; fusion Families of gene fusions tend to characterize specific cancer protein that is composed of the transactivation domain of types. -
Hsa-Mir-125B-2 Is Highly Expressed in Childhood ETV6&Sol;RUNX1
Leukemia (2010) 24, 89–96 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 $32.00 www.nature.com/leu ORIGINAL ARTICLE Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53 N Gefen1,2,8, V Binder1,3,8, M Zaliova4, Y Linka3, M Morrow6, A Novosel3, L Edry5, L Hertzberg1,2,7, N Shomron5, O Williams6, J Trka4, A Borkhardt3 and S Izraeli1,2 1Section of Functional Genomics and Leukemia Research, Department of Pediatric Hemato-Oncology, Sheba Medical Center, Tel-Hashomer, Israel; 2Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Department of Pediatric Hematology, Oncology and Immunology, Heinrich Heine University, Duesseldorf, Germany; 4Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Childhood Leukemia Investigation Prague, Prague, Czech Republic; 5Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 6Institute of Child Health, University College London, London, UK and 7Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel MicroRNAs (miRNAs) regulate the expression of multiple characterized by an intrachromosomal amplification of a small proteins in a dose-dependent manner. We hypothesized that region within the long arm of chr 21 (iAMP21) around the increased expression of miRNAs encoded on chromosome 21 4 (chr 21) contribute to the leukemogenic function of trisomy 21. RUNX1 locus. In contrast to ETV6/RUNX1 and HHD ALL, it is The levels of chr 21 miRNAs were quantified by qRT–PCR in associated with poor prognosis. -
The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19
International Journal of Molecular Sciences Review The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19 Alessandro Bellis 1 , Ciro Mauro 1, Emanuele Barbato 2, Bruno Trimarco 2 and Carmine Morisco 2,* 1 Unità Operativa Complessa Cardiologia con UTIC ed Emodinamica-Dipartimento Emergenza Accettazione, Azienda Ospedaliera “Antonio Cardarelli”, 80131 Napoli, Italy; [email protected] (A.B.); [email protected] (C.M.) 2 Dipartimento di Scienze Biomediche Avanzate, Università FEDERICO II, 80131 Napoli, Italy; [email protected] (E.B.); [email protected] (B.T.) * Correspondence: [email protected]; Tel.: +39-081-746-2253; Fax: +39-081-746-2256 Received: 12 October 2020; Accepted: 11 November 2020; Published: 15 November 2020 Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger “cytokine storm” leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on “multi-targeted” therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. -
Markers for Detection of Prostate Cancer
Cancers 2010, 2, 1125-1154; doi:10.3390/cancers2021125 OPEN ACCESS cancers ISSN 2072-6694 www.mdpi.com/journal/cancers Review Markers for Detection of Prostate Cancer Raymond A. Clarke 1, Horst J. Schirra 2, James W. Catto 3, Martin F. Lavin 4,5 and Robert A. Gardiner 5,* 1 Prostate Cancer Institute, Cancer Care Centre, St George Hospital Clinical School of Medicine, University of New South Wales, Kogarah, NSW 2217, Australia; E-Mail: [email protected] 2 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD, 4072, Australia; E-Mail: [email protected] 3 Academic Urology Unit and Institute for Cancer Studies, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; E-Mail: [email protected] 4 Queensland Institute of Medical Research, Radiation Biology and Oncology, Brisbane, QLD 4029, Australia; E-Mail: [email protected] 5 University of Queensland Centre for Clinical Research, Brisbane, Australia * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 22 March 2010; in revised form: 2 June 2010 / Accepted: 3 June 2010 / Published: 4 June 2010 Abstract: Early detection of prostate cancer is problematic, not just because of uncertainly whether a diagnosis will benefit an individual patient, but also as a result of the imprecise and invasive nature of establishing a diagnosis by biopsy. Despite its low sensitivity and specificity for identifying patients harbouring prostate cancer, serum prostate specific antigen (PSA) has become established as the most reliable and widely-used diagnostic marker for this condition. In its wake, many other markers have been described and evaluated. -
Transcription of Nrdp1 by the Androgen Receptor Is Regulated by Nuclear filamin a in Prostate Cancer
R M Savoy et al. Nrdp1 is an AR target regulated 22:3 369–386 Research by FLNA Transcription of Nrdp1 by the androgen receptor is regulated by nuclear filamin A in prostate cancer Rosalinda M Savoy1,2, Liqun Chen2, Salma Siddiqui1, Frank U Melgoza1, Blythe Durbin- Johnson3, Christiana Drake4, Maitreyee K Jathal1,2, Swagata Bose1,2, Thomas M Steele1, Benjamin A Mooso1, Leandro S D’Abronzo1,2, William H Fry5, Kermit L Carraway III5, Maria Mudryj1,6 and Paramita M Ghosh1,2,5 1VA Northern California Health Care System, Mather, California, USA 2Department of Urology, School of Medicine, University of California Davis, 4860 Y Street, Suite 3500, Correspondence Sacramento, California 95817, USA should be addressed 3Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, California, USA to P M Ghosh 4Department of Statistics, University of California Davis, Davis, California, USA Email 5Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, California, USA paramita.ghosh@ucdmc. 6Department of Medical Microbiology and Immunology, University of California Davis, Davis, California, USA ucdavis.edu Abstract Prostate cancer (PCa) progression is regulated by the androgen receptor (AR); however, Key Words patients undergoing androgen-deprivation therapy (ADT) for disseminated PCa eventually " castration-resistant prostate develop castration-resistant PCa (CRPC). Results of previous studies indicated that AR,a cancer transcription factor, occupies distinct genomic loci in CRPC compared with hormone-naı¨ve " AR/androgen receptor " Endocrine-Related Cancer PCa; however, the cause of this distinction was unknown. The E3 ubiquitin ligase Nrdp1 is a FLRF/RNF41/Nrdp1 model AR target modulated by androgens in hormone-naı¨ve PCa but not in CRPC. -
S01-01 Therapeutic Targeting of TMPRSS2 and ACE2 As a Potential Strategy to Combat COVID-19. Qu Deng1, Reyaz Ur Rasool1, Ramakrishnan Natesan1, Irfan A
S01-01 Therapeutic targeting of TMPRSS2 and ACE2 as a potential strategy to combat COVID-19. Qu Deng1, Reyaz Ur Rasool1, Ramakrishnan Natesan1, Irfan A. Asangani2. 1Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 2Department of Cancer Biology, Abramson Family Cancer Research Institute, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. The novel SARS-CoV-2 infection responsible for the COVID-19 pandemic is expected to have an adverse effect on the progression of multiple cancers, including prostate cancer, due to the ensuing cytokine storm associated oncogenic signaling. A better understanding of the host cell factors and their regulators will help identify potential therapies to block SARS-CoV-2 infection at an early stage and thereby prevent cancer progression. Host cell infection by SARS-CoV-2 requires the binding of the viral spike S protein to ACE2 receptor and priming by the serine protease TMPRSS2—encoded by a well-known androgen response gene and highly expressed in patients diagnosed with prostate cancer. Epidemiologic data showing increased severity and mortality of SARS-CoV-2 disease in men suggest a possible role for androgen in the transcriptional activation of ACE2 and TMPRSS2 in the lungs and other primary infection sites. Here, by performing in vivo castration in mice, RT-PCR, immunoblotting, Co-IP, and pseudovirus infection assays in multiple cell lines, we present evidence for the transcriptional regulation of TMPRSS2 and ACE2 by androgen, their endogenous interaction, as well as a novel combination of drugs in blocking viral infection. In adult male mice, castration led to a significant loss in the expression of ACE2 and TMPRSS2 at the transcript and protein levels in the lung, heart, and small intestine. -
HDAC3: Taking the SMRT-N-Correct Road to Repression
Oncogene (2007) 26, 5439–5449 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW HDAC3: taking the SMRT-N-CoRrect road to repression P Karagianni and J Wong1 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA Known histone deacetylases (HDACs) are divided into repression when targeted to promoters, as well as different classes, and HDAC3 belongs to Class I. Through physical association with the DNA-binding factor forming multiprotein complexes with the corepressors YY1 (Yang et al., 1997; Dangond et al., 1998; Emiliani SMRT and N-CoR, HDAC3 regulates the transcription et al., 1998). Together, these findings suggested that this of a plethora of genes. A growing list of nonhistone ubiquitously expressed protein could be involved in the substrates extends the role of HDAC3 beyond transcrip- regulation of mammalian gene expression. On the other tional repression. Here, we review data on the composi- hand, HDAC3 contains an intriguingly variable C tion, regulation and mechanism of action of the SMRT/ terminus, with no apparent similarity with other N-CoR-HDAC3 complexes and provide several examples HDACs. This observation led to the hypothesis that of nontranscriptional functions, to illustrate the wide HDAC3 may have some unique properties and may variety of physiological processes affected by this deacety- not be completely redundant with the other HDACs lase. Furthermore, we discuss the implication of HDAC3 (Yang et al., 1997). This is also suggested by the in cancer, focusing on leukemia. We conclude with some differential localization of HDAC3, which, unlike the thoughts about the potential therapeutic efficacies of predominantly nuclear HDACs 1 and 2, can be found in HDAC3 activity modulation. -
The Complex Genetic Landscape of Familial MDS and AML Reveals Pathogenic Germline Variants
ARTICLE https://doi.org/10.1038/s41467-020-14829-5 OPEN The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants Ana Rio-Machin et al.# The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and 1234567890():,; myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 pre- viously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management. #A full list of authors and their affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2020) 11:1044 | https://doi.org/10.1038/s41467-020-14829-5 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-14829-5 nherited forms of myeloid malignancies are thought to be rare, Results Ialthough the precise -
Molecular Pathways: Targeting ETS Gene Fusions in Cancer
Published OnlineFirst June 23, 2014; DOI: 10.1158/1078-0432.CCR-13-0275 Clinical Cancer Molecular Pathways Research Molecular Pathways: Targeting ETS Gene Fusions in Cancer Felix Y. Feng1,2,3, J. Chad Brenner2,3,4,5, Maha Hussain3,6,7, and Arul M. Chinnaiyan2,3,4,7,8 Abstract Rearrangements, or gene fusions, involving the ETS family of transcription factors are common driving events in both prostate cancer and Ewing sarcoma. These rearrangements result in pathogenic expression of the ETS genes and trigger activation of transcriptional programs enriched for invasion and other oncogenic features. Although ETS gene fusions represent intriguing therapeutic targets, transcription factors, such as those comprising the ETS family, have been notoriously difficult to target. Recently, preclinical studies have demonstrated an association between ETS gene fusions and components of the DNA damage response pathway, such as PARP1, the catalytic subunit of DNA protein kinase (DNAPK), and histone deactylase 1 (HDAC1), and have suggested that ETS fusions may confer sensitivity to inhibitors of these DNA repair proteins. In this review, we discuss the role of ETS fusions in cancer, the preclinical rationale for targeting ETS fusions with inhibitors of PARP1, DNAPK, and HDAC1, as well as ongoing clinical trials targeting ETS gene fusions. Clin Cancer Res; 20(17); 4442–8. Ó2014 AACR. Background tion domain (from the EWS gene) to the ETS fusion and ETS transcription factors are aberrantly expressed in (ii) replacement of the N-terminus of the ETS protein by several cancers, including prostate cancer (1), the Ewing an RNA-binding domain from the EWS protein that sarcoma family of tumors (2), melanoma (3), secretory enhances posttranscriptional splicing of ETS target genes breast carcinoma (4), acute lymphoblastic leukemia (5), (10; Fig. -
An Integrative Approach Reveals Genetic Complexity and Epigenetic
Human Pathology (2019) 91,1–10 www.elsevier.com/locate/humpath Original contribution An integrative approach reveals genetic complexity and epigenetic perturbation in acute promyelocytic leukemia: a single institution experience☆ Nina Rahimi MD a,YanmingZhangMDb, Alain Mina MD c, Jessica K. Altman MD c, Madina Sukhanova PhD a, Olga Frankfurt MD c, Lawrence Jennings MD, PhD a, Xinyan Lu MD a,AmirBehdadMDa, Qing Chen MD, PhD a, Yi-Hua Chen MD a, Juehua Gao MD, PhD a,⁎ aDepartment of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA bDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA cDepartment of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA Received 10 March 2019; revised 8 May 2019; accepted 8 May 2019 Keywords: Summary Acute promyelocytic leukemia (APL) is a distinct type of acute myeloid leukemia that is Acute promyelocytic defined by the presence of the translocations that mostly involve the RARA gene. The most frequent leukemia; translocation is the t(15;17), which fuses the RARA gene with the PML gene. Previous studies have Next-generation shown that other cooperative mutations are required for the development of APL after the initiating sequencing; event of the t(15;17). In this study, we combined cytogenetics with next-generation sequencing and Somatic mutations; single-nucleotide polymorphism array to study the genetic complexity in 20 APL cases diagnosed in our in- SNP array; stitution. All but 3 cases had additional genetic aberrations. Our study demonstrated that somatic mutations Copy neutral loss of are frequent events in APL.