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The Biological Impact of Novel Dual Methyltransferase Inhibitors The biological impact of novel dual histone methyltransferase inhibitors Ian Lewis Green MSci (Hons) University of Aberdeen CID: 00718112 Division of Cancer Department of Surgery & Cancer Imperial College London Thesis submitted for the degree of Doctor of Philosophy 2015 1 Declaration of Originality I, Ian Green, hereby declare that this PhD thesis is my own work. In the preparation of this manuscript all references have been consulted by me. Except where specifically stated, the work presented in this thesis was performed by me. Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives license. Researchers are free to copy distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the license terms of this work. 2 Abstract Background: EZH2 is a histone methyltransferase (HKMT) responsible for the maintenance of epigenetic silencing of genes through maintenance of the repressive H3K27me3 mark and it is aberrantly regulated in numerous cancers, including breast cancer where it is linked to aggressive phenotypes and poor clinical outcomes. EHMT2 is a related HKMT responsible for gene silencing by mediating H3K9me3 levels. EHMT2 is also responsible for H3K27me1 and has been shown to physically interact with EZH2. Specific inhibitors of EZH2 are available and have been shown to be effective in cancers with EZH2 mutation driven phenotypes (e.g. follicular lymphoma) but have shown limited efficacy in epithelial cancers. Here we present the characterisation of novel dual HKMT inhibitors targeting both EZH2 and EHMT2, which we believe will have a greater impact than individual inhibitors in reversing EZH2 mediated silencing. Results: Utilising publicly available data, we show expression of EZH2 and related subunits of the PRC2 complex and related EHMT2/EHMT1 complex range greatly in normal tissue, but EZH2 and EHMT2 expression are consistently up-regulated in numerous cancers. We show that CNV and mutation of EZH2 and EHMT2 infrequently occur in breast cancer- however, in breast cancer high expression of EZH2 is linked to reduced RFS and OS of patients. In breast cancer cell lines, dual HKMT inhibitors up-regulate EZH2 target genes, in gene specific and genome wide manner, to a greater degree than EZH2 or EHMT2 inhibition alone and induce expression of genes associated with apoptotic pathways. This up-regulation of silenced genes occurs concurrently with a decrease in H3K27me3 and H3K9me3 levels on target genes. In breast cancer cells and ovarian cancer cells, dual HKMT inhibitors reduce cell clonogenicity, 3 cancer stem cell activity, cancer stem cell self-renewal capacity, and sensitise cancer stem cells to Paclitaxel and Cisplatin treatment. Conclusions: Novel dual inhibitors of EZH2 and EHMT2 alter gene expression and inhibit cell growth and cancer stem cell activity in wild-type EZH2 tumour cells. These data support the further preclinical and clinical evaluation of such inhibitors in triple negative breast cancer and epithelial ovarian cancer. 4 Acknowledgements I would like to acknowledge foremost Professor Bob Brown and Dr Ed Curry, who have supervised me throughout this project. Their unceasing support, guidance, and belief have allowed this project to move forward- I cannot express my gratitude enough. Nadine Chapman-Rothe acted as my secondary supervisor during the initial phases of this project and provided help and collaboration with ChIP-PCR experiments, and was succeeded by Constanze Zeller whose enthusiasm and support was a great resource. Elham Shamsaei and Sarah Kandil both worked a great deal on this project, and helped drive it forward to where it is now. MRes students Emma Bell and Luke Payne both worked on this project as part of their studies, and their input is something for which I am very grateful. Collaborators Anthony Uren from the MRC Clinical Sciences Centre, Gillian Farnie and Amrita Shergill from University of Manchester all provided wonderful expertise in their fields and their collaboration allowed this project to move in interesting and exciting directions. Any acknowledgements to specific experimental work are highlighted within this thesis. Fanny Cherblanc, Thota Ganesh, Nitipol Srimongkolpithak, Joachim Caron, Fengling Li, James P Snyder, Masoud Vedadi, and Pete Dimaggio have all worked around the chemistry of these novel inhibitors, and without them this work would not have been possible- their efforts were orchestrated by Matt Fuchter, whose enthusiasm for the project has helped unearth many avenues of subsequent research. 5 The wonderful collection of postdocs in the epigenetics group (or nearby…) were an invaluable source of knowledge, ideas, and coffee- Erick Loomis, Kirsty Flower, Charlotte Wilhelm- Benartzi, Paula Cunnea, Elaina Maginn, Fieke Froeling, Nair Bonito- thank you all. Fellow students Jane Borley, Natalie Shenker, Angela Wilson, Kevin Brennan, Alun Passy, Kayleigh Davis and David Phelps have all be lovely with their time and feedback and friendship. Nahal Masrour has been a constantly helpful presence, and James Flanagan has been more than helpful with his input and critical eye. CRUK provided me with my studentship, administered by Jennifer Podesta, without which this work would have been impossible, and OCA and Imperial College provided me with the space, environment, and colleagues which allowed this work to be completed. Copenhagen Biosciences subsidised my attendance to the Copenhagen Biosciences Stem Cell Niche conference 2014 in Copenhagen, which was a wonderful opportunity to see some first class research. My parents and brothers have shown unfailing support and encouragement and patience, and their belief has been a continuing source of comfort and resilience. Finally Abi, without who I would have probably died of scurvy at about the 18 month mark, and for all the other obvious reasons. 6 Contents Declaration of Originality .............................................................................................................. 2 Copyright Declaration ................................................................................................................... 2 Abstract .......................................................................................................................................... 3 Acknowledgements ....................................................................................................................... 5 Contents ......................................................................................................................................... 7 List of figures ............................................................................................................................... 12 List of tables ................................................................................................................................ 13 Abbreviations ............................................................................................................................... 14 Peer reviewed publications and presentations ............................................................................. 17 Chapter 1: Introduction ............................................................................................................ 18 1.1 Overview of epigenetics and cancer ......................................................................... 18 1.1.1- Overview .................................................................................................................. 18 1.1.2- Epigenetic therapies and pathways in cancer ....................................................... 19 1.2 The HKMT EZH2 ........................................................................................................... 20 1.2.1- H3K27me3 and HKMTs ......................................................................................... 20 1.3 EZH2 and cancer ........................................................................................................ 22 1.3.1 EZH2 and cancer ................................................................................................. 22 1.3.2 EZH2 and EHMT2 .............................................................................................. 25 7 1.4 Cancer stem cells and EZH2 ...................................................................................... 27 1.5 Identification of novel dual HKMT ........................................................................... 30 Hypothesis .............................................................................................................................. 34 Aims ........................................................................................................................................ 34 Chapter 2: Materials and methods ............................................................................................... 35 Cell culture .......................................................................................................................... 35 RNA preparation .................................................................................................................. 35 QRT-PCR ...........................................................................................................................
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