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The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc Oncogenesis

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The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc Oncogenesis The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc oncogenesis By Yuting Sun This thesis is submitted in fulfilment of the requirements for the degree of Doctor of Philosophy at the University of New South Wales Children’s Cancer Institute Australia for Medical Research School of Women’s and Children’s Health, Faculty of Medicine University of New South Wales Australia August 2014 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Sun First name: Yuting Other name/s: Abbreviation for degree as given in the University calendar: PhD School : School of·Women's and Children's Health Faculty: Faculty of Medicine Title: The Roles of Histone Deacetylase 5 and the Histone Methyltransferase Adaptor WDR5 in Myc oncogenesis. Abstract 350 words maximum: (PLEASE TYPE) N-Myc Induces neuroblastoma by regulating the expression of target genes and proteins, and N-Myc protein is degraded by Fbxw7 and NEDD4 and stabilized by Aurora A. The class lla histone deacetylase HDAC5 suppresses gene transcription, and blocks myoblast and leukaemia cell differentiation. While histone H3 lysine 4 (H3K4) trimethylation at target gene promoters is a pre-requisite for Myc· induced transcriptional activation, WDRS, as a histone H3K4 methyltransferase presenter, is required for H3K4 methylation and transcriptional activation mediated by a histone H3K4 methyltransferase complex. Here, I investigated the roles of HDAC5 and WDR5 in N-Myc overexpressing neuroblastoma. I have found that N-Myc upregulates HDAC5 protein expression, and that HDAC5 represses NEDD4 gene expression, increases Aurora A gene expression and consequently upregulates N-Myc protein expression in neuroblastoma cells. HDAC5 and N-Myc commonly repress the expression of a subset of genes by forming a protein · ~omplex, while HDAC5 and the class Ill HDAC SIRT2 commonly, but Independently, repress the expression of another subset of genes. Moreover, HDAC5 blocks cell differentiation and Induces cell proliferation. I have also demonstrated that N-Myc upregulates WDRS gene expression by binding to the WDR5 gene promoter. Conversely, WDR5 forms a protein complex with N·Myc at the gene promoter of N-Myc target genes, leading to histone H3K4 trimethylation and transcriptional activation of N-Myc target genes, Including MDM2 and CCNE1. Importantly, WDR5 reduces the expression of wild type, but not mutant, p53 protein expression In MYCN oncogene-amplified neuroblastoma cells through reducing MDM2 expression, induces neuroblastoma cell proliferation in p53 dependent/independent fashions, and enhances neuroblastoma cell survival in a p53-dependent manner. In a publicly available large cohort of 476 neuroblastoma patients, high levels of WDR5 gene expression in tumours correlate with poor patient survival independent of MYCN amplification and disease stage. In addition, treatment with WDR5 inhibitors blocks the formation of N-Myc and WDR5 protein complex, reduces the expression of N-Myc and WDR5 target genes, and impedes neuroblastoma cell proliferation. In conclusion, these data Identify HDAC5 and WDR5 as novel co-factors in N-Myc oncogenesis, and provide the critical evidence for the potential utilization of WDR5 inhibitors for the therapy of neuroblastoma. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only) . ..... -:: ...•. ~ ·· ; ········ ... ~J ..?. ~.l .~.. !.. lf. ..... Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing . Requests for a longer period of restriction may be considered in exceptional circumstances and re uire the a rova l of the Dean of Graduate Research. FOR OFFICE USE ONLY Da te of com pletion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ORIGINALITY STATEMENT 'I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or :i:::·p~~~~~ledged' Date ..........1.§. / .~.~... /.~ .. ~ .. Y.:. .. .......... COPYRIGHT STATEMENT 'I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed Date .............7/.S .J .. Q .. 8... /.. ±-:9.. Ltf.......... ................ AUTHENTICITY STATEMENT 'I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the :::~ion~.di~~~~. ........ .... Date .. .............J& ./. ... ~ ..fr. ./ .... ~ .Q . .l ..tj:: ......... ....... .. ... Table of content TABLE OF CONTENT ............................................................................................ I LIST OF TABLES .............................................................................................. VIII LIST OF FIGURES ................................................................................................ IX ABSTRACT ......................................................................................................... XIII ABBREVIATIONS .............................................................................................. XV PUBLICATIONS ................................................................................................. XXI PRESENTATIONS ............................................................................................. XXII ACKNOWLEDGMENTS ................................................................................. XXIV CHAPTER 1 INTRODUCTION ............................................................................. 1 1.1 GENERAL INTRODUCTION ............................................................................................... 2 1.2 MYC ONCOGENESIS ....................................................................................................... 4 1.2.1 Myc protein structure ...................................................................................... 7 1.2.2 Myc oncoproteins enhance transcriptional activation .................................... 7 1.2.3 Myc-mediated transcriptional repression ....................................................... 9 1.2.4 Myc paradoxically induces apoptosis ............................................................ 13 1.2.5 Myc induces cell proliferation ........................................................................ 14 1.2.6 Myc blocks cell differentiation ....................................................................... 15 1.2.7 Targeting Myc for cancer treatment .............................................................. 16 1.3 NEUROBLASTOMA ...................................................................................................... 18 1.3.1 Staging and Classification ............................................................................... 19 i 1.3.2 Genetic abnormalities .................................................................................... 21 1.3.3 Amplification of MYCN oncogene .................................................................. 23 1.3.4 p53 in neuroblastoma .................................................................................... 24 1.3.5 Cell differentiation block in neuroblastoma .................................................. 27 1.3.6 Current neuroblastoma therapy .................................................................... 29 1.4 HISTONE
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