DOCSLIB.ORG

The Microtubule-Associated Protein PRC1 Promotes Early Recurrence Of

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

Gut Online First, published on March 3, 2016 as 10.1136/gutjnl-2015-310625 Hepatology ORIGINAL ARTICLE The microtubule-associated protein PRC1 promotes Gut: first published as 10.1136/gutjnl-2015-310625 on 3 March 2016. Downloaded from early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway Jianxiang Chen,1,2 Muthukumar Rajasekaran,1 Hongping Xia,1 Xiaoqian Zhang,2 Shik Nie Kong,1 Karthik Sekar,1 Veerabrahma Pratap Seshachalam,1 Amudha Deivasigamani,1 Brian Kim Poh Goh,3 London Lucien Ooi,3 Wanjin Hong,2 Kam M Hui1,2,4,5 ▸ Additional material is ABSTRACT published online only. To view Objectives Hepatocellular carcinoma (HCC) is the Significance of this study please visit the journal online (http://dx.doi.org/10.1136/ second leading cause of cancer mortality worldwide. gutjnl-2015-310625). Alterations in microtubule-associated proteins (MAPs) have been observed in HCC. However, the mechanisms For numbered affiliations see What is already known on this subject? end of article. underlying these alterations remain poorly understood. ▸ Early recurrence in human hepatocellular Our aim was to study the roles of the MAP protein carcinoma (HCC) remains the major cause of Correspondence to regulator of cytokinesis 1 (PRC1) in hepatocarcinogenesis death after potentially curative liver resection. Professor Kam M Hui, Division and early HCC recurrence. ▸ Protein regulator of cytokinesis 1 (PRC1) of Cellular and Molecular Research, National Cancer Design PRC1 expression in HCC samples was regulates antiparallel microtubule cross-linking Centre, 11 Hospital Drive, evaluated by microarray, immunoblotting and to promote the formation of microtubule Singapore 169610, Singapore; immunohistochemistry analysis. Molecular and cellular architectures to support cell shape and regulate [email protected] techniques including siRNA-mediated and lentiviral cytokinesis. PRC1 has been reported to be vector-mediated knockdown were used to elucidate the Received 25 August 2015 upregulated in breast and bladder tumours. Revised 11 February 2016 functions and mechanisms of PRC1. ▸ The Wnt-β-catenin network is enormously Accepted 12 February 2016 Results PRC1 expression was associated with early complex. Aberrant regulation of the canonical HCC recurrence and poor patient outcome. In HCC, Wnt-β-catenin signalling pathway is associated http://gut.bmj.com/ PRC1 exerted an oncogenic effect by promoting cancer with a variety of diseases, including cancer, proliferation, stemness, metastasis and tumourigenesis. fibrosis and neurodegeneration. There are two We further demonstrated that the expression and types of HCC in which β-catenin signalling are distribution of PRC1 is dynamically regulated by Wnt3a activated. In both cases, nuclear β-catenin is signalling. PRC1 knockdown impaired transcription factor found with a specific transcriptional output. In (TCF) transcriptional activity, decreased Wnt target the first type, this is due to CTNNB1 activating on September 27, 2021 by guest. Protected copyright. expression and reduced nuclear β-catenin levels. mutations and the HCCs are mostly well Mechanistically, PRC1 interacts with the β-catenin differentiated with a rather good prognosis: destruction complex, regulates Wnt3a-induced these tumours overexpress glutamine membrane sequestration of this destruction complex, synthetase, which is a highly specific and inhibits adenomatous polyposis coli (APC) stability and highly sensitive marker of β-catenin mutation. promotes β-catenin release from the APC complex. In The second type of tumours is Wnt-activated vivo, high PRC1 expression correlated with nuclear β- and is mostly not CTNNB1-mutated: they catenin and Wnt target expression. PRC1 acted as a correspond to HCC with a poorer prognosis. master regulator of a set of 48 previously identified Wnt- regulated recurrence-associated genes (WRRAGs) in HCC. Thus, PRC1 controlled the expression and function the poor survival of patients with HCC and is the 3–5 of WRRAGs such as FANCI, SPC25, KIF11 and KIF23 via major obstacle to improving prognosis. Despite Wnt signalling. the recent reports elucidating signalling regulators 67 Conclusions We identified PRC1 as a novel Wnt target related to early HCC recurrence, the underlying that functions in a positive feedback loop that reinforces signalling network remains largely unknown. Wnt signalling to promote early HCC recurrence. Among the growth factor signalling cascades that are deregulated in HCC, evidence suggests that the – canonical Wnt signalling pathway8 11 plays a key 12–20 To cite: Chen J, role in hepatocarcinogenesis. Rajasekaran M, Xia H, et al. INTRODUCTION Microtubules (MTs) play essential roles in cell Gut Published Online First: Hepatocellular carcinoma (HCC) is the second cycle, trafficking, signalling and migration. [please include Day Month leading cause of cancer mortality worldwide.12 Alterations in MT-associated proteins (MAPs) have Year] doi:10.1136/gutjnl- 2015-310625 Early HCC recurrence is primarily responsible for been demonstrated in cancers, and these changes Chen J, et al. Gut 2016;0:1–13. doi:10.1136/gutjnl-2015-310625 1 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd (& BSG) under licence. Hepatology were provided by the SingHealth Tissue Repository. Written fi informed consent was obtained from the participating patients, Signi cance of this study Gut: first published as 10.1136/gutjnl-2015-310625 on 3 March 2016. Downloaded from and relevant clinical and histopathological data provided to the researchers were anonymised. The antibodies for this study are fi listed in online supplementary table S1. Microarray was per- What are the new ndings? 7 ▸ PRC1 is upregulated in HCC, especially in early recurrent formed as described previously. HCC. ▸ PRC1 has an oncogenic function in promoting cancer proliferation, stemness, metastasis and tumourigenesis. Animal studies ▸ PRC1 is a direct Wnt signalling target, and its cytoskeletal Stably transfected HCCLM3 cells were resuspended in phos- localisation is dynamically regulated by Wnt3a activity. phate-buffered saline (PBS) and subcutaneously implanted into ▸ PRC1 is necessary for Wnt signalling to mediate the left and right flanks (5×106 cells per flank) of male BALB/c oncogenesis and cancer stem cells self-renewal. nude mice. Tumour volume was monitored and calculated as ▸ PRC1 potentiates Wnt signalling by promoting the described previously.25 membrane sequestration of the Axin1 destruction complex, Additional materials and methods are provided in online sup- thereby reducing APC stability but stabilising β-catenin. plementary information. ▸ Wnt-regulated recurrence-associated genes (WRRAGs) were identified in HCC, and PRC1 regulated the expression of WRRAGs via Wnt signalling. RESULTS How might it impact on clinical practice in the PRC1 is upregulated in HCC and its expression correlates foreseeable future? with early HCC recurrence ▸ The PRC1-coordinated WRRAG cluster might be useful as a Based on the results from data mining of our microarray data- predictor of the risk of early HCC recurrence and as an base previously established,7 PRC1 expression was significantly indicator of Wnt signalling activities. upregulated in HCC tumours compared with histologically ▸ Abundant clinical evidence has implicated a critical role of normal liver (NN) from colorectal cancer patients with liver aberrant canonical Wnt/β-catenin signalling in HCC initiation metastases or matched adjacent histologically normal liver (MN) and development, underscoring the potential of targeting tissues (p<0.001; figure 1A, left panel). PRC1 expression in a this pathway for the therapeutic intervention of this typically subset of these samples was further validated by real-time PCR difficult-to-treat cancer. In this study, PRC1 emerged as a (see online supplementary figure S1A). In addition, PRC1 new therapeutic target, and its microtubule-binding domain expression was markedly upregulated in tumours from patients could be targeted using small molecule inhibitors. Specific with early (<2 years) recurrent disease (HCC-R) compared with small molecule inhibitors or activators with defined targets samples from patients with no demonstrable evidence of recur- rence within 5 years (HCC-NR) (p<0.001; figure 1A, right and mechanisms would provide therapeutic leads for HCC http://gut.bmj.com/ and research tools to manipulate the Wnt pathway in panel). PRC1 expression in a subset of these HCC-NR samples precise temporal and spatial ways. was also validated (see online supplementary figure S1B). Furthermore, data mining of RNA-seq data from HCC and adja- generally correlate with poor prognosis. A role for a divergent cent matched tissues that are publically available in The Cancer fi canonical Wnt pathway in regulating the MT cytoskeleton to Genome Atlas database con rmed that PRC1 expression is sig- fi promote cell movement has been suggested,21 implying that ni cantly elevated in tumours compared with matched normal fi fi on September 27, 2021 by guest. Protected copyright. MAPs may be involved in Wnt signalling by interacting with tissues (p<0.001; gure 1B). Signi cantly higher PRC1 expres- Wnt components. This suggestion is supported by the observa- sion levels were detected in tumours exhibiting more frequent fi tion that many Wnt pathway components, including APC, vascular invasion (see online supplementary gure S1C) and in Axin1 and GSK3β, are associated with MTs.21 However, little is those scored as high-grade cancer (see
Recommended publications
  • A Midbody Component Homolog, Too Much Information/Prc1-Like, Is Required For

    A Midbody Component Homolog, Too Much Information/Prc1-Like, Is Required For

    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.10.447958; this version posted June 11, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. A midbody component homolog, too much information/prc1-like, is required for microtubule reorganization during both cytokinesis and axis induction in the early zebrafish embryo Nair, S 1,2,*, 1Welch, E.L. 1,*, Moravec, C.E. 1, Trevena, R.L.1, Pelegri, F. 1 * shared first authorship 1. LaBoratory of Genetics, University of Wisconsin-Madison, Madison, WI, USA 2. Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India Correspondence to: Francisco Pelegri at [email protected] 608-262-2920 Short title: zebrafish Prc-1L, cytokinesis and axis induction Key words: zebrafish, Prc-1, cytokinesis, midBody, microtuBule reorganization, axis induction bioRxiv preprint doi: https://doi.org/10.1101/2021.06.10.447958; this version posted June 11, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Abstract We show that the zeBrafish maternal-effect mutation too much information (tmi) corresponds to zebrafish prc1-like (prc1l), which encodes a member of the MAP65/Ase1/PRC1family of microtuBule-associated proteins. Embryos from tmi/prc1l homozygous mutant mothers display cytokinesis defects in meiotic and mitotic divisions in the early embryo, indicating that tmi/prc1l has a role in midBody formation during cell division at the egg-to-embryo transition. Unexpectedly, maternal tmi/prc1l function is also essential for the reorganization of vegetal pole microtuBules required for embryonic axis induction.
  • A Key Genomic Signature Associated with Lymphovascular Invasion in Head and Neck Squamous Cell Carcinoma

    A Key Genomic Signature Associated with Lymphovascular Invasion in Head and Neck Squamous Cell Carcinoma

    A key genomic signature associated with lymphovascular invasion in head and neck squamous cell carcinoma Jian Zhang Aliated Cancer hospital & Institute of Guangzhou Medical University Huali Jiang Aliated Donghua Hospital of Sun Yat-sen University Tao Xie Aliated Cancer Hospital of Guangzhou Medical University Baiyao Wang Aliated Cancer Hospital of Guangzhou Medical Unversity Xiaoting Huang Aliated Cancer Hospital & Institute of Guangzhou Medical University Jie Lin Aliated Cancer Hospital & Institute of Guangzhou Medical University Anan Xu Aliated Cancer Hospital of Guangzhou Medical University Rong Li Aliated Cancer Hospital & Institute of Guangzhou Medical University Yawei Yuan ( [email protected] ) Guangzhou Medical University Aliated Cancer Hospital Research article Keywords: lymphovascular invasion, head and neck squamous cell carcinoma, hub genes, TCGA, weighted gene co-expression network analysis Posted Date: January 16th, 2020 DOI: https://doi.org/10.21203/rs.2.18349/v2 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/24 Abstract Objective: Lymphovascular invasion (LOI), a key pathological feature of head and neck squamous cell carcinoma (HNSCC), predicts poor survival. However, the associated clinical characteristics remain uncertain, and the molecular mechanisms are largely unknown. Methods: Weighted gene co-expression network analysis was performed to construct gene co-expression networks and investigate the relationship between modules and LOI clinical trait. Functional enrichment and KEGG pathway enrichment analysis were performed for differentially expressed genes using DAVID database. The protein-protein interaction network was constructed using Cytoscape software, and module analysis was performed using MCODE. Prognosis role and expression analysis was further validated by survival analysis, GEPIA analysis and HPA database.
  • Transcriptional Regulation of the P16 Tumor Suppressor Gene

    Transcriptional Regulation of the P16 Tumor Suppressor Gene

    ANTICANCER RESEARCH 35: 4397-4402 (2015) Review Transcriptional Regulation of the p16 Tumor Suppressor Gene YOJIRO KOTAKE, MADOKA NAEMURA, CHIHIRO MURASAKI, YASUTOSHI INOUE and HARUNA OKAMOTO Department of Biological and Environmental Chemistry, Faculty of Humanity-Oriented Science and Engineering, Kinki University, Fukuoka, Japan Abstract. The p16 tumor suppressor gene encodes a specifically bind to and inhibit the activity of cyclin-CDK specific inhibitor of cyclin-dependent kinase (CDK) 4 and 6 complexes, thus preventing G1-to-S progression (4, 5). and is found altered in a wide range of human cancers. p16 Among these CKIs, p16 plays a pivotal role in the regulation plays a pivotal role in tumor suppressor networks through of cellular senescence through inhibition of CDK4/6 activity inducing cellular senescence that acts as a barrier to (6, 7). Cellular senescence acts as a barrier to oncogenic cellular transformation by oncogenic signals. p16 protein is transformation induced by oncogenic signals, such as relatively stable and its expression is primary regulated by activating RAS mutations, and is achieved by accumulation transcriptional control. Polycomb group (PcG) proteins of p16 (Figure 1) (8-10). The loss of p16 function is, associate with the p16 locus in a long non-coding RNA, therefore, thought to lead to carcinogenesis. Indeed, many ANRIL-dependent manner, leading to repression of p16 studies have shown that the p16 gene is frequently mutated transcription. YB1, a transcription factor, also represses the or silenced in various human cancers (11-14). p16 transcription through direct association with its Although many studies have led to a deeper understanding promoter region.
  • Polycomb Repressor Complex 2 Function in Breast Cancer (Review)

    Polycomb Repressor Complex 2 Function in Breast Cancer (Review)

    INTERNATIONAL JOURNAL OF ONCOLOGY 57: 1085-1094, 2020 Polycomb repressor complex 2 function in breast cancer (Review) COURTNEY J. MARTIN and ROGER A. MOOREHEAD Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON N1G2W1, Canada Received July 10, 2020; Accepted September 7, 2020 DOI: 10.3892/ijo.2020.5122 Abstract. Epigenetic modifications are important contributors 1. Introduction to the regulation of genes within the chromatin. The poly- comb repressive complex 2 (PRC2) is a multi‑subunit protein Epigenetic modifications, including DNA methylation complex that is involved in silencing gene expression through and histone modifications, play an important role in gene the trimethylation of lysine 27 at histone 3 (H3K27me3). The regulation. The dysregulation of these modifications can dysregulation of this modification has been associated with result in pathogenicity, including tumorigenicity. Research tumorigenicity through the increased repression of tumour has indicated an important influence of the trimethylation suppressor genes via condensing DNA to reduce access to the modification at lysine 27 on histone H3 (H3K27me3) within transcription start site (TSS) within tumor suppressor gene chromatin. This methylation is involved in the repression promoters. In the present review, the core proteins of PRC2, as of multiple genes within the genome by condensing DNA well as key accessory proteins, will be described. In addition, to reduce access to the transcription start site (TSS) within mechanisms controlling the recruitment of the PRC2 complex gene promoter sequences (1). The recruitment of H1.2, an H1 to H3K27 will be outlined. Finally, literature identifying the histone subtype, by the H3K27me3 modification has been a role of PRC2 in breast cancer proliferation, apoptosis and suggested as a mechanism for mediating this compaction (1).
  • Apoptotic Genes As Potential Markers of Metastatic Phenotype in Human Osteosarcoma Cell Lines

    Apoptotic Genes As Potential Markers of Metastatic Phenotype in Human Osteosarcoma Cell Lines

    17-31 10/12/07 14:53 Page 17 INTERNATIONAL JOURNAL OF ONCOLOGY 32: 17-31, 2008 17 Apoptotic genes as potential markers of metastatic phenotype in human osteosarcoma cell lines CINZIA ZUCCHINI1, ANNA ROCCHI2, MARIA CRISTINA MANARA2, PAOLA DE SANCTIS1, CRISTINA CAPANNI3, MICHELE BIANCHINI1, PAOLO CARINCI1, KATIA SCOTLANDI2 and LUISA VALVASSORI1 1Dipartimento di Istologia, Embriologia e Biologia Applicata, Università di Bologna, Via Belmeloro 8, 40126 Bologna; 2Laboratorio di Ricerca Oncologica, Istituti Ortopedici Rizzoli; 3IGM-CNR, Unit of Bologna, c/o Istituti Ortopedici Rizzoli, Via di Barbiano 1/10, 40136 Bologna, Italy Received May 29, 2007; Accepted July 19, 2007 Abstract. Metastasis is the most frequent cause of death among malignant primitive bone tumor, usually developing in children patients with osteosarcoma. We have previously demonstrated and adolescents, with a high tendency to metastasize (2). in independent experiments that the forced expression of Metastases in osteosarcoma patients spread through peripheral L/B/K ALP and CD99 in U-2 OS osteosarcoma cell lines blood very early and colonize primarily the lung, and later markedly reduces the metastatic ability of these cancer cells. other skeleton districts (3). Since disseminated hidden micro- This behavior makes these cell lines a useful model to assess metastases are present in 80-90% of OS patients at the time the intersection of multiple and independent gene expression of diagnosis, the identification of markers of invasiveness signatures concerning the biological problem of dissemination. and metastasis forms a target of paramount importance in With the aim to characterize a common transcriptional profile planning the treatment of osteosarcoma lesions and enhancing reflecting the essential features of metastatic behavior, we the prognosis.
  • Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates

    Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates

    Research Article Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates David Gius,1 Margo C. Funk,2 Eric Y. Chuang,1 Sheng Feng,3 Phyllis C. Huettner,4 Loan Nguyen,2 C. Matthew Bradbury,1 Mark Mishra,1 Shuping Gao,1 Barbara M. Buttin,2 David E. Cohn,2 Matthew A. Powell,2 Neil S. Horowitz,2 Bradford P. Whitcomb,2 and JanetS. Rader 2 1Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland and 2Division of Gynecologic Oncology, Department of Obstetrics and Gynecology; 3Division of Biostatistics; and 4Lauren V. Ackerman Laboratory of Surgical Pathology, Washington University School of Medicine, St. Louis, Missouri Abstract (CIN 1–3) and finally to squamous cell carcinoma antigen (SCCA) This study is the first comprehensive, integrated approach to have been well characterized. Histologically, CIN 1 consists of examine grade-specific changes in gene expression along the immature basal-type cells involving the lower third of the entire neoplastic spectrum of cervical intraepithelial neoplasia epithelium. In CIN 2, these immature basal-type cells involve more (CIN) in the process of cervical carcinogenesis. This was than the lower third, whereas CIN 3 involves the full thickness of the accomplished by identifying gene expression signatures of epithelium. In addition, higher CIN grades exhibit nuclear crowding, disease progression using cDNA microarrays to analyze RNA pleomorphism, loss of cell polarity, and increased mitotic activity from laser-captured microdissected epithelium and underlying (1). These transitions seemto be well conserved and, as such, stroma from normal cervix, graded CINs, cancer, and patient- provide an intriguing systemto use genomicsto identify the early matched normal cervical tissues.
  • A Dissertation Entitled the Androgen Receptor

    A Dissertation Entitled the Androgen Receptor

    A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen.
  • Plasma Cells in Vitro Generation of Long-Lived Human

    Plasma Cells in Vitro Generation of Long-Lived Human

    Downloaded from http://www.jimmunol.org/ by guest on September 24, 2021 is online at: average * The Journal of Immunology , 32 of which you can access for free at: 2012; 189:5773-5785; Prepublished online 16 from submission to initial decision 4 weeks from acceptance to publication November 2012; doi: 10.4049/jimmunol.1103720 http://www.jimmunol.org/content/189/12/5773 In Vitro Generation of Long-lived Human Plasma Cells Mario Cocco, Sophie Stephenson, Matthew A. Care, Darren Newton, Nicholas A. Barnes, Adam Davison, Andy Rawstron, David R. Westhead, Gina M. Doody and Reuben M. Tooze J Immunol cites 65 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription http://www.jimmunol.org/content/suppl/2012/11/16/jimmunol.110372 0.DC1 This article http://www.jimmunol.org/content/189/12/5773.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 24, 2021. The Journal of Immunology In Vitro Generation of Long-lived Human Plasma Cells Mario Cocco,*,1 Sophie Stephenson,*,1 Matthew A.
  • KIF23 Enhances Cell Proliferation in Pancreatic Ductal Adenocarcinoma and Is a Potent Therapeutic Target

    KIF23 Enhances Cell Proliferation in Pancreatic Ductal Adenocarcinoma and Is a Potent Therapeutic Target

    1394 Original Article Page 1 of 15 KIF23 enhances cell proliferation in pancreatic ductal adenocarcinoma and is a potent therapeutic target Chun-Tao Gao1#, Jin Ren2#, Jie Yu1,3#, Sheng-Nan Li1, Xiao-Fan Guo1, Yi-Zhang Zhou1 1Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China; 2Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China; 3The First Hospital of Shanxi Medical University, Taiyuan, China Contributions: (I) Conception and design: CT Gao, J Ren; (II) Administrative support: CT Gao; (III) Provision of study materials or patients: J Yu; (IV) Collection and assembly of data: J Ren, SN Li, YZ Zhou; (V) Data analysis and interpretation: XF Guo, J Ren; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. #These authors contributed equally to this work. Correspondence to: Chun-Tao Gao. Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Huan-hu-xi Road, He-xi District, Tianjin 300060, China. Email: [email protected]. Background: In recent research, high expression of kinesin family member 23 (KIF23), one of the kinesin motor proteins involved in the regulation of cytokinesis, has been shown to be related to poor prognosis in glioma and paclitaxel-resistant gastric cancer, as a results of the enhancement of proliferation, migration, and invasion. In this study, we analyzed the role of KIF23 in the progression of pancreatic ductal adenocarcinoma.
  • EZH2 in Normal Hematopoiesis and Hematological Malignancies

    EZH2 in Normal Hematopoiesis and Hematological Malignancies

    www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 3 EZH2 in normal hematopoiesis and hematological malignancies Laurie Herviou2, Giacomo Cavalli2, Guillaume Cartron3,4, Bernard Klein1,2,3 and Jérôme Moreaux1,2,3 1 Department of Biological Hematology, CHU Montpellier, Montpellier, France 2 Institute of Human Genetics, CNRS UPR1142, Montpellier, France 3 University of Montpellier 1, UFR de Médecine, Montpellier, France 4 Department of Clinical Hematology, CHU Montpellier, Montpellier, France Correspondence to: Jérôme Moreaux, email: [email protected] Keywords: hematological malignancies, EZH2, Polycomb complex, therapeutic target Received: August 07, 2015 Accepted: October 14, 2015 Published: October 20, 2015 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the Polycomb repressive complex 2, inhibits gene expression through methylation on lysine 27 of histone H3. EZH2 regulates normal hematopoietic stem cell self-renewal and differentiation. EZH2 also controls normal B cell differentiation. EZH2 deregulation has been described in many cancer types including hematological malignancies. Specific small molecules have been recently developed to exploit the oncogenic addiction of tumor cells to EZH2. Their therapeutic potential is currently under evaluation. This review summarizes the roles of EZH2 in normal and pathologic hematological processes and recent advances in the development of EZH2 inhibitors for the personalized treatment of patients with hematological malignancies. PHYSIOLOGICAL FUNCTIONS OF EZH2 state through tri-methylation of lysine 27 on histone H3 (H3K27me3) [6].
  • How Does SUMO Participate in Spindle Organization?

    How Does SUMO Participate in Spindle Organization?

    cells Review How Does SUMO Participate in Spindle Organization? Ariane Abrieu * and Dimitris Liakopoulos * CRBM, CNRS UMR5237, Université de Montpellier, 1919 route de Mende, 34090 Montpellier, France * Correspondence: [email protected] (A.A.); [email protected] (D.L.) Received: 5 July 2019; Accepted: 30 July 2019; Published: 31 July 2019 Abstract: The ubiquitin-like protein SUMO is a regulator involved in most cellular mechanisms. Recent studies have discovered new modes of function for this protein. Of particular interest is the ability of SUMO to organize proteins in larger assemblies, as well as the role of SUMO-dependent ubiquitylation in their disassembly. These mechanisms have been largely described in the context of DNA repair, transcriptional regulation, or signaling, while much less is known on how SUMO facilitates organization of microtubule-dependent processes during mitosis. Remarkably however, SUMO has been known for a long time to modify kinetochore proteins, while more recently, extensive proteomic screens have identified a large number of microtubule- and spindle-associated proteins that are SUMOylated. The aim of this review is to focus on the possible role of SUMOylation in organization of the spindle and kinetochore complexes. We summarize mitotic and microtubule/spindle-associated proteins that have been identified as SUMO conjugates and present examples regarding their regulation by SUMO. Moreover, we discuss the possible contribution of SUMOylation in organization of larger protein assemblies on the spindle, as well as the role of SUMO-targeted ubiquitylation in control of kinetochore assembly and function. Finally, we propose future directions regarding the study of SUMOylation in regulation of spindle organization and examine the potential of SUMO and SUMO-mediated degradation as target for antimitotic-based therapies.
  • Genomics and Functional Genomics of Malignant Pleural Mesothelioma

    Genomics and Functional Genomics of Malignant Pleural Mesothelioma

    International Journal of Molecular Sciences Review Genomics and Functional Genomics of Malignant Pleural Mesothelioma Ece Cakiroglu 1,2 and Serif Senturk 1,2,* 1 Izmir Biomedicine and Genome Center, Izmir 35340, Turkey; [email protected] 2 Department of Genome Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35340, Turkey * Correspondence: [email protected] Received: 22 July 2020; Accepted: 20 August 2020; Published: 1 September 2020 Abstract: Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is strongly associated with prior exposure to asbestos fibers, and the median survival rate of the diagnosed patients is approximately one year. Despite the latest advancements in surgical techniques and systemic therapies, currently available treatment modalities of MPM fail to provide long-term survival. The increasing incidence of MPM highlights the need for finding effective treatments. Targeted therapies offer personalized treatments in many cancers. However, targeted therapy in MPM is not recommended by clinical guidelines mainly because of poor target definition. A better understanding of the molecular and cellular mechanisms and the predictors of poor clinical outcomes of MPM is required to identify novel targets and develop precise and effective treatments. Recent advances in the genomics and functional genomics fields have provided groundbreaking insights into the genomic and molecular profiles of MPM and enabled the functional characterization of the genetic alterations. This review provides a comprehensive overview of the relevant literature and highlights the potential of state-of-the-art genomics and functional genomics research to facilitate the development of novel diagnostics and therapeutic modalities in MPM.