DOCSLIB.ORG

1 Up-Regulation of Rac Gtpase Activating Protein 1 Is Significantly

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
1 Up-Regulation of Rac Gtpase Activating Protein 1 Is Significantly Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RACGAP1 and HCC recurrence Up-regulation of Rac GTPase activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma Suk Mei Wang1, London Lucien P.J. Ooi2, and Kam M. Hui1,3 Authors' Affiliations: 1Bek Chai Heah Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; 2Department of Surgical Oncology, National Cancer Centre, Singapore and 3Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore. Corresponding Author: Kam M. Hui, Division of Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610; Phone: (65) 6436-8337; Fax: (65) 6226-3843; E-mail: [email protected]. Running title: RACGAP1 and HCC recurrence Key words: human hepatocellular carcinoma; interactome; oligonucleotide gene arrays; prediction of recurrent HCC disease; RACGAP1. Abbreviations: RACGAP1, Rac GTPase activating protein 1; HCC, hepatocellular carcinoma; HBV, Hepatitis B virus; HCV, Hepatitis C virus; AFP, alpha-fetoprotein. Grant support: This work was supported by grants from the National Medical Research Council, Biomedical Research Council of Singapore and The Singapore Millennium Foundation. 1 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RACGAP1 and HCC recurrence Translational Relevance Hepatocellular carcinoma (HCC) is the world’s third commonest cause of cancer-related deaths. Surgery currently offers the only possibility of long-term survival for these patients. Unfortunately, recurrences occur in more than two thirds of these patients and confer a dismal prognosis. In this study, we have systematically presented molecular evidence and provided clinical corroboration of these data to demonstrate that, independently from clinical risk factors, aggressive early recurrent HCC tumors have their Rac GTPase-activating protein 1 (RACGAP1) expression significantly up-regulated. For the first time, our data provides clinical support for possible drug developments targeting the various important oncogenic signaling molecules in an interactome clinically relevant to early HCC recurrence. Our results also suggest the importance of RACGAP1 as a stratification factor for the design of future comparative therapeutic trials which is especially important for early recurrent HCC tumors. 2 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RACGAP1 and HCC recurrence Abstract Purpose: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease. Experimental Design: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1 targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes. Results: Kaplan-Meier analysis demonstrated that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of post-resection recurrent HCC (p<0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using IPA, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1 and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts were analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly up-regulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results. Conclusions: siRNA silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. 3 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RACGAP1 and HCC recurrence Introduction Hepatocellular carcinoma (HCC) is the commonest primary cancer of the liver and is the world’s third most frequent cause of cancer-related deaths, with more than 660,000 deaths per annum (1-5). The major etiological factors of HCC are hepatitis B virus (HBV) and hepatitis C virus infection (HCV), and various other non-viral related causes such as aflatoxins, alcohol intake and other causes of liver cirrhosis including non-alcoholic steatohepatitis (NASH). The prevalence of HCC in Europe and the US is increasing and is currently the leading cause of death in patients with cirrhosis, possibly resulting from the transmission of HCV by intravenous drug abuse and a rising prevalence of obesity and diabetes (6, 7). Surgery currently offers the only possibility of prolonged survival for HCC patients. Unfortunately, recurrence occurs in more than two-thirds of these patients despite initial curative intent and converts the situation to a dismal prognosis (8, 9). It is presently a challenge to identify patients who are at high risk for early recurrence after undergoing potentially curative treatment for HCC and various surrogate clinicopathological features like lymphovascular invasion, capsular invasion, satellite lesions and tumour numbers are often used with varying reliability. Such high risk patients could potentially benefit from closer surveillance or receive adjuvant novel interventional measures if they could be accurately identified. DNA microarrays have been widely applied to the study of human cancer and comprehensive and systematic functional analyses of large number of genetic and epigenetic alterations provide unbiased analytical approaches to decipher the molecular heterogeneity of cancer (10, 11). Through these strategies, distinct subclasses of HCC patients based on their differing gene expression patterns, which were also associated with patient survival, were identified, indicating the 4 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. RACGAP1 and HCC recurrence presence of distinct molecular subtypes of HCC (12-14). However, the identification of the early recurrence of HCC remains a major challenge and the development of new prognostic markers are urgently needed to identify HCC patients who are at higher risk of having recurrence. Previous studies by our group and others have successfully shown that specific gene expression signatures can be established from frozen and formalin-fixed cancerous tissues to accurately predict early recurrent disease following curative hepatic surgery (15-19). In this context, we have reported a 57-member gene signature earlier for selecting HCC patients who are at higher risk of having recurrent disease (18). While a number of options for gene set analysis exist, we have chosen to investigate the prognostic significance of individual members of the gene set using multivariate and log rank test and observed that RACGAP1, a member of this 57-member gene signature, gave the best ability to predict early recurrent disease and survival outcome. In this study, we report the identification and molecular characterization of RACGAP1 as a clinically relevant prognostic predictor for recurrent HCC disease. Materials and Methods Patient samples All tissue samples employed in this study were approved and provided by the Tissue Repository of the National Cancer Centre Singapore and conducted in accordance with the policies of its Ethics Committee. Informed consent was obtained from all participating patients and all clinical and histopathological data provided to the researchers were rendered anonymous. Cancerous and some of the corresponding distant 5 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2011 American Association for Cancer Research. Author Manuscript Published OnlineFirst on August 8, 2011; DOI: 10.1158/1078-0432.CCR-11-0557 Author manuscripts have been peer reviewed and accepted for publication
Load more

Recommended publications
  • Systems Analysis Implicates WAVE2&Nbsp
    JACC: BASIC TO TRANSLATIONAL SCIENCE VOL.5,NO.4,2020 ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/). PRECLINICAL RESEARCH Systems Analysis Implicates WAVE2 Complex in the Pathogenesis of Developmental Left-Sided Obstructive Heart Defects a b b b Jonathan J. Edwards, MD, Andrew D. Rouillard, PHD, Nicolas F. Fernandez, PHD, Zichen Wang, PHD, b c d d Alexander Lachmann, PHD, Sunita S. Shankaran, PHD, Brent W. Bisgrove, PHD, Bradley Demarest, MS, e f g h Nahid Turan, PHD, Deepak Srivastava, MD, Daniel Bernstein, MD, John Deanfield, MD, h i j k Alessandro Giardini, MD, PHD, George Porter, MD, PHD, Richard Kim, MD, Amy E. Roberts, MD, k l m m,n Jane W. Newburger, MD, MPH, Elizabeth Goldmuntz, MD, Martina Brueckner, MD, Richard P. Lifton, MD, PHD, o,p,q r,s t d Christine E. Seidman, MD, Wendy K. Chung, MD, PHD, Martin Tristani-Firouzi, MD, H. Joseph Yost, PHD, b u,v Avi Ma’ayan, PHD, Bruce D. Gelb, MD VISUAL ABSTRACT Edwards, J.J. et al. J Am Coll Cardiol Basic Trans Science. 2020;5(4):376–86. ISSN 2452-302X https://doi.org/10.1016/j.jacbts.2020.01.012 JACC: BASIC TO TRANSLATIONALSCIENCEVOL.5,NO.4,2020 Edwards et al. 377 APRIL 2020:376– 86 WAVE2 Complex in LVOTO HIGHLIGHTS ABBREVIATIONS AND ACRONYMS Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes.
    [Show full text]
  • 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.
    [Show full text]
  • IL21R Expressing CD14+CD16+ Monocytes Expand in Multiple
    Plasma Cell Disorders SUPPLEMENTARY APPENDIX IL21R expressing CD14 +CD16 + monocytes expand in multiple myeloma patients leading to increased osteoclasts Marina Bolzoni, 1 Domenica Ronchetti, 2,3 Paola Storti, 1,4 Gaetano Donofrio, 5 Valentina Marchica, 1,4 Federica Costa, 1 Luca Agnelli, 2,3 Denise Toscani, 1 Rosanna Vescovini, 1 Katia Todoerti, 6 Sabrina Bonomini, 7 Gabriella Sammarelli, 1,7 Andrea Vecchi, 8 Daniela Guasco, 1 Fabrizio Accardi, 1,7 Benedetta Dalla Palma, 1,7 Barbara Gamberi, 9 Carlo Ferrari, 8 Antonino Neri, 2,3 Franco Aversa 1,4,7 and Nicola Giuliani 1,4,7 1Myeloma Unit, Dept. of Medicine and Surgery, University of Parma; 2Dept. of Oncology and Hemato-Oncology, University of Milan; 3Hematology Unit, “Fondazione IRCCS Ca’ Granda”, Ospedale Maggiore Policlinico, Milan; 4CoreLab, University Hospital of Parma; 5Dept. of Medical-Veterinary Science, University of Parma; 6Laboratory of Pre-clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture; 7Hematology and BMT Center, University Hospital of Parma; 8Infectious Disease Unit, University Hospital of Parma and 9“Dip. Oncologico e Tecnologie Avanzate”, IRCCS Arcispedale Santa Maria Nuova, Reggio Emilia, Italy ©2017 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2016.153841 Received: August 5, 2016. Accepted: December 23, 2016. Pre-published: January 5, 2017. Correspondence: [email protected] SUPPLEMENTAL METHODS Immunophenotype of BM CD14+ in patients with monoclonal gammopathies. Briefly, 100 μl of total BM aspirate was incubated in the dark with anti-human HLA-DR-PE (clone L243; BD), anti-human CD14-PerCP-Cy 5.5, anti-human CD16-PE-Cy7 (clone B73.1; BD) and anti-human CD45-APC-H 7 (clone 2D1; BD) for 20 min.
    [Show full text]
  • 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.
    [Show full text]
  • 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).
    [Show full text]
  • 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].
    [Show full text]
  • Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of Ivig in Allergic Airways Disease
    Published February 20, 2017, doi:10.4049/jimmunol.1502361 The Journal of Immunology Peripherally Generated Foxp3+ Regulatory T Cells Mediate the Immunomodulatory Effects of IVIg in Allergic Airways Disease Amir H. Massoud,*,†,1 Gabriel N. Kaufman,* Di Xue,* Marianne Be´land,* Marieme Dembele,* Ciriaco A. Piccirillo,‡ Walid Mourad,† and Bruce D. Mazer* IVIg is widely used as an immunomodulatory therapy. We have recently demonstrated that IVIg protects against airway hyper- responsiveness (AHR) and inflammation in mouse models of allergic airways disease (AAD), associated with induction of Foxp3+ regulatory T cells (Treg). Using mice carrying a DTR/EGFP transgene under the control of the Foxp3 promoter (DEREG mice), we demonstrate in this study that IVIg generates a de novo population of peripheral Treg (pTreg) in the absence of endogenous Treg. IVIg-generated pTreg were sufficient for inhibition of OVA-induced AHR in an Ag-driven murine model of AAD. In the absence of endogenous Treg, IVIg failed to confer protection against AHR and airway inflammation. Adoptive transfer of purified IVIg-generated pTreg prior to Ag challenge effectively prevented airway inflammation and AHR in an Ag-specific manner. Microarray gene expression profiling of IVIg-generated pTreg revealed upregulation of genes associated with cell cycle, chroma- tin, cytoskeleton/motility, immunity, and apoptosis. These data demonstrate the importance of Treg in regulating AAD and show that IVIg-generated pTreg are necessary and sufficient for inhibition of allergen-induced AAD. The ability of IVIg to generate pure populations of highly Ag-specific pTreg represents a new avenue to study pTreg, the cross-talk between humoral and cellular immunity, and regulation of the inflammatory response to Ags.
    [Show full text]
  • Dysregulation of Mitotic Machinery Genes Precedes Genome Instability
    The Author(s) BMC Genomics 2016, 17(Suppl 8):728 DOI 10.1186/s12864-016-3068-5 RESEARCH Open Access Dysregulation of mitotic machinery genes precedes genome instability during spontaneous pre-malignant transformation of mouse ovarian surface epithelial cells Ulises Urzúa1*, Sandra Ampuero2, Katherine F. Roby3, Garrison A. Owens4,6 and David J. Munroe4,5 From 6th SolBio International Conference 2016 (SoIBio-IC&W-2016) Riviera Maya, Mexico. 22-26 April 2016 Abstract Background: Based in epidemiological evidence, repetitive ovulation has been proposed to play a role in the origin of ovarian cancer by inducing an aberrant wound rupture-repair process of the ovarian surface epithelium (OSE). Accordingly, long term cultures of isolated OSE cells undergo in vitro spontaneous transformation thus developing tumorigenic capacity upon extensive subcultivation. In this work, C57BL/6 mouse OSE (MOSE) cells were cultured up to passage 28 and their RNA and DNA copy number profiles obtained at passages 2, 5, 7, 10, 14, 18, 23, 25 and 28 by means of DNA microarrays. Gene ontology, pathway and network analyses were focused in passages earlier than 20, which is a hallmark of malignancy in this model. Results: At passage 14, 101 genes were up-regulated in absence of significant DNA copy number changes. Among these, the top-3 enriched functions (>30 fold, adj p < 0.05) comprised 7 genes coding for centralspindlin, chromosome passenger and minichromosome maintenance protein complexes. The genes Ccnb1 (Cyclin B1), Birc5 (Survivin), Nusap1 and Kif23 were the most recurrent in over a dozen GO terms related to the mitotic process. On the other hand, Pten plus the large non-coding RNAs Malat1 and Neat1 were among the 80 down-regulated genes with mRNA processing, nuclear bodies, ER-stress response and tumor suppression as relevant terms.
    [Show full text]
  • The Central Role of EED in the Orchestration of Polycomb Group Complexes
    ARTICLE Received 22 Aug 2013 | Accepted 16 Dec 2013 | Published 24 Jan 2014 DOI: 10.1038/ncomms4127 The central role of EED in the orchestration of polycomb group complexes Qi Cao1,2,3,4, Xiaoju Wang1,2, Meng Zhao5, Rendong Yang5, Rohit Malik1,2, Yuanyuan Qiao1,2, Anton Poliakov1,2, Anastasia K. Yocum1, Yong Li1, Wei Chen1,6, Xuhong Cao1,7, Xia Jiang1,2, Arun Dahiya1, Clair Harris8, Felix Y. Feng1,6,9, Sundeep Kalantry8, Zhaohui S. Qin5,10, Saravana M. Dhanasekaran1,2 & Arul M. Chinnaiyan1,2,7,9,11 Polycomb repressive complexes 1 and 2 (PRC1 and 2) play a critical role in the epigenetic regulation of transcription during cellular differentiation, stem cell pluripotency and neoplastic progression. Here we show that the polycomb group protein EED, a core component of PRC2, physically interacts with and functions as part of PRC1. Components of PRC1 and PRC2 compete for EED binding. EED functions to recruit PRC1 to H3K27me3 loci and enhances PRC1-mediated H2A ubiquitin E3 ligase activity. Taken together, we suggest an integral role for EED as an epigenetic exchange factor coordinating the activities of PRC1 and 2. 1 Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 2 Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. 3 Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas 77030, USA. 4 Cancer Center, Houston Methodist Research Institute, Houston, Texas 77030, USA. 5 Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA. 6 Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
    [Show full text]
  • Identification of Novel Biomarkers in Hepatocellular Carcinoma By
    Identication of Novel Biomarkers in Hepatocellular Carcinoma by Integrated Bioinformatical Analysis and Experimental Validation Chen Liao Yunnan University of Traditional Chinese Medicine Lanlan Wang Shaanxi University of Chinese Medicine Xiaoqiang Li Fourth Military Medical University Department of Social Sciences: Air Force Medical University Jinyu Bai Yunnan University of Traditional Chinese Medicine Jieqiong Wu Shaanxi University of Chinese Medicine Wei Zhang Shaanxi University of Chinese Medicine Hailong Shi Shaanxi University of Chinese Medicine Xuesong Feng Shaanxi University of Chinese Medicine Xu Chao ( [email protected] ) Shaanxi University of Chinese Medicine https://orcid.org/0000-0001-5520-4834 Research Keywords: Hepatocellular carcinoma, novel biomarkers, candidate small molecules, prognosis, bioinformatics analysis Posted Date: June 16th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-533830/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/14 Abstract Background: Hepatocellular carcinoma (HCC) is one of the most common poorly prognosed virulent neoplasms of the digestive system. In this study, we identied novel biomarkers associated with the pathogenesis of HCC aiming to provide new diagnostic and therapeutic approaches for HCC. Methods: Gene expression proles of GSE62232, GSE84402,GSE121248 and GSE45267 were obtained in GEO database. Differential expressed genes (DEGs) between HCC and normal samples were identied using the GEO2R tool and Venn diagram software.Database for Annotation, Visualization and Integrated Discovery (DAVID) were used to carry out enrichment analysis on gene ontology (GO) and the Kyoto Encyclopaedia of Genes and Genomes pathway (KEGG). The protein-protein interaction (PPI) network of DEGs was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING) and visualized by Cytoscape.
    [Show full text]
  • Juxtaposed Polycomb Complexes Co-Regulate Vertebral Identity
    RESEARCH ARTICLE 4957 Development 133, 4957-4968 (2006) doi:10.1242/dev.02677 Juxtaposed Polycomb complexes co-regulate vertebral identity Se Young Kim1, Suzanne W. Paylor1, Terry Magnuson2 and Armin Schumacher1,* Best known as epigenetic repressors of developmental Hox gene transcription, Polycomb complexes alter chromatin structure by means of post-translational modification of histone tails. Depending on the cellular context, Polycomb complexes of diverse composition and function exhibit cooperative interaction or hierarchical interdependency at target loci. The present study interrogated the genetic, biochemical and molecular interaction of BMI1 and EED, pivotal constituents of heterologous Polycomb complexes, in the regulation of vertebral identity during mouse development. Despite a significant overlap in dosage-sensitive homeotic phenotypes and co-repression of a similar set of Hox genes, genetic analysis implicated eed and Bmi1 in parallel pathways, which converge at the level of Hox gene regulation. Whereas EED and BMI1 formed separate biochemical entities with EzH2 and Ring1B, respectively, in mid-gestation embryos, YY1 engaged in both Polycomb complexes. Strikingly, methylated lysine 27 of histone H3 (H3-K27), a mediator of Polycomb complex recruitment to target genes, stably associated with the EED complex during the maintenance phase of Hox gene repression. Juxtaposed EED and BMI1 complexes, along with YY1 and methylated H3- K27, were detected in upstream regulatory regions of Hoxc8 and Hoxa5. The combined data suggest a model wherein epigenetic and genetic elements cooperatively recruit and retain juxtaposed Polycomb complexes in mammalian Hox gene clusters toward co- regulation of vertebral identity. KEY WORDS: Polycomb, eed, Bmi1, Hox genes, Mouse development, Chromatin, Histones, Epigenetics INTRODUCTION Wang, H.
    [Show full text]
  • Novel Targets of Apparently Idiopathic Male Infertility
    International Journal of Molecular Sciences Review Molecular Biology of Spermatogenesis: Novel Targets of Apparently Idiopathic Male Infertility Rossella Cannarella * , Rosita A. Condorelli , Laura M. Mongioì, Sandro La Vignera * and Aldo E. Calogero Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; [email protected] (R.A.C.); [email protected] (L.M.M.); [email protected] (A.E.C.) * Correspondence: [email protected] (R.C.); [email protected] (S.L.V.) Received: 8 February 2020; Accepted: 2 March 2020; Published: 3 March 2020 Abstract: Male infertility affects half of infertile couples and, currently, a relevant percentage of cases of male infertility is considered as idiopathic. Although the male contribution to human fertilization has traditionally been restricted to sperm DNA, current evidence suggest that a relevant number of sperm transcripts and proteins are involved in acrosome reactions, sperm-oocyte fusion and, once released into the oocyte, embryo growth and development. The aim of this review is to provide updated and comprehensive insight into the molecular biology of spermatogenesis, including evidence on spermatogenetic failure and underlining the role of the sperm-carried molecular factors involved in oocyte fertilization and embryo growth. This represents the first step in the identification of new possible diagnostic and, possibly, therapeutic markers in the field of apparently idiopathic male infertility. Keywords: spermatogenetic failure; embryo growth; male infertility; spermatogenesis; recurrent pregnancy loss; sperm proteome; DNA fragmentation; sperm transcriptome 1. Introduction Infertility is a widespread condition in industrialized countries, affecting up to 15% of couples of childbearing age [1]. It is defined as the inability to achieve conception after 1–2 years of unprotected sexual intercourse [2].
    [Show full text]