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Nuclear Receptor Co-Repressor Functions in Prostate Cancer; in Vitro, in Vivo and in Silico Approaches

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Nuclear Receptor Co-Repressor Functions in Prostate Cancer; in Vitro, in Vivo and in Silico Approaches Nuclear receptor co-repressor functions in prostate cancer; in vitro, in vivo and in silico approaches By Sebastiano Battaglia A thesis presented to the School of Medicine, University of Birmingham, For the degree of Doctor of Philosophy. School of Medicie Institute for Biomedical Research University of Birmingham July 2009 1 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Summary SUMMARY Nuclear Receptor CoRepressor-1 (NCOR1) controls the actions of multiple transcription factors including nuclear receptors (NR). The prostate malignant cell line PC-3, displays a significant differential expression of a cohort of corepressors (NCOR1, RIP140, LCOR, SLIRP) and subsequent loss of responsiveness to NR ligands, including those for PPAR and VDR, compared to the non-malignant cell line RWPE1 at a transcriptional and phenotypical level. NR insensitivity can be antagonized by using the histone deacetylase inhibitor SAHA in combination with the PPARα and -γ ligand bezafibrate. Microarray approaches revealed co-treatment restored PPAR transcriptional actions towards target genes (e.g. CDKN1A, PTGS2, ALOX5, CDC2, TGFBRAP1). NCOR1-knock down by shRNA restored partially the transcriptional abilities of PPARs upon treatment with bezafibrate, mimicking the effect of SAHA on the genes identified. Interestingly, shNCOR1-PC-3 were more sensitive towards the PPARα and PPARγ ligands, ETYA and EPA respectively, but were unresponsive to 1,25(OH)2-D3 and T3. This was reflected at the transcriptional level where in bezafibrate-treated shNCOR1-PC-3 the expression of PPAR target genes (TGFBRAP1, CDKN1A, ALOX5, CDC2) was restored mirroring the activity of SAHA. To profile the transcriptome regulated by NCOR1 during the cell cycle a microfluidic gene card approach was undertaken. PC-3 cells were FACS sorted in G1, S and G2 phases and demonstrated that shNCOR1-PC-3 cells restored the Basal levels of key regulators of cell viability such as histone modifiers, CDKN1A, TP53 and CDH1. ChIP analysis in siNCOR1-PC-3 cells also revealed that NCOR1 controls the epigenetic modifications at the CDKN1A and TGFBRAP1 TSS differentially modulating H3K9 acetylation upon bezafibrate treatment, reflecting mRNA accumulation data. The contribution of NCOR1 and NCOR2/SMRT in prostate development is unknown. To identify these functions more accurately Ncor1, and Ncor2/Smrt, are being knocked out in mice in prostate-specific manner using a Cre/Lox-P strategy where the Cre enzyme is controlled by the modified prostate-specific rat probasin promoter, ARR2PB. 2 Summary CDKN1A is an example of a gene differentially regulated by bezafibrate in shNCOR1- PC-3, non responsive to 1,25(OH)2-D3 in wild type PC-3 and significantly induced in non malignant RWPE1 cells. To understand this complex regulation, and predict the regulatory mechanism of CDKN1A transcription, we sought to create an ordinary differential equations (ODE) model of the initial transcriptional events on the TSS of the CDKN1A gene in RWPE1 cells. We fitted time course data hypothesizing that a poised phospho-RNA PolII bound at the promoter region could explain a quick and steep induction in mRNA production followed by an equal steep degradation mediated by the miRNA miR-106B. This model will be used to interrogate malignant cell responses to NR ligands. 3 This thesis is dedicated to my great parents and to my awesome sister! …VAI TRA… 4 Aknowledgments AKNOWLEDGMENTS There is a long list of people that I should thank for the help, the support and the friendship that they gave me during these last three years. Without them I probably would not be where I am right now, personally and professionally; I will name these people following the chronological order in which I met them during my wandering around Europe, hopping between universities, PCRs and happy hours. First off, a great thanks goes to my supervisors: Dr. Moray Campbell (also for teaching me how to be a “committed disinterested observer”) and Dr. Chris Bunce for the support, for the patience that they had, for the friendship that they offered and for the passion they shared with me! I want also to thank Dr. Chris McCabe for the supervision he offered me during my last period in Birmingham and for the great time playing guitar! I want to thank James Thorne for helping me during my very first days in Birmingham, inside and outside the lab; Asad Abedin for being the first person, with James, that taught me molecular biology techniques; Farhat Khanim for always being present when we had troubles in the lab and for always supporting me even when stuff was not working; Dr. Francesco Falciani for introducing me to the world of Bioinformatics and to the “Italian community”; Craig Doig and Pedro Velica for sharing great times in the lab and many pints in the pub; all the people at the IBR especially Caroline, Greg, Vicky, Sally, Rowan, Rachel, Jo Tucka, Olly, Ellen, Yin, Mark Sherlock, Phil, Kirren, Gareth (also for all the training sessions), Liz Rabbit, Ana, Matt, Clare, and all the other that share with me great moments. I definitely want to thank friends (and colleagues) like Giacomo, Fra Crea, Cristiano, Andrea (entrambi), Walter, Anna, Stefano Cogo, Vasillio & Angeliki, Eugenio, 5 Aknowledgments Steph, Marco Falco and Alberto “limone” Sesa for the invaluable friendship and the memorable moments that we spent together! One thanks goes to my great ex-flatmates Ashley and Clare; to Bob Spour to open my eyes on Muay Thai and for writing one of my tattoos and thanks to Andy for the great time teaching Muay Thai at the University and for bringing me to Wales! During about 11 months spent in Berlin at the Max Plank Institute I could have never achieved what I did without the great support of Dr. Heiner Schrewe, Pedro Rocha, Mia Mayer and Manuela Scholze. They not only helped me to develop the Ncor constructs but they were always ready to answer my questions and patiently explain to me what to do even if they were busy and my questions were silly! All the people at the Max Plank have been really open and friendly with me, I would like to thank Mark, Benny, Joanna, Markus, Philip, Ive, Arnold, Nathalie, Shini, Jurgen, Hermann and all those that I cannot member but I met at the MPI. Moreover, I was lucky enough to meet a unique group of people outside the lab that greatly supported me in pursuing my way as a scientist and as a better person, I will never forget Matteo that gave me a house when I didn’t have one and still is a great friend; Jens that shared with me unforgivable moments and was next to me when I needed and hope to meet him soon; Simon (you are the man) for always being a great scientist/person and friend; Lisa that helped me growing, she was the first one to teach me to look beyond the surface of myself and others and showed me a deeper way of living; my ex-flatmates Simon and Miriam for helping me to cheer up after a day of work; Dan, whom I spent a great time with; and Dinara for the insightful discussions that luckily we still have. 6 Aknowledgments I spent about a month at the University of Luxembourg where I moved my first steps in systems biology. Here a great thanks goes to Prof. Carsten Calberg and his team that warmly welcomed me and helped me to settle down; thanks to Katjia and Aleksandra, fellow ESRs and friends, for the professional and personal support; and thanks to Prof. Thomas Sauter for the suggestions on my model and for the everyday cheerful chats. I moved to the Roswell Park Cancer Institute for the last two months of my PhD. Here, apart from my supervisor Dr. Moray Campbell and Craig that are always great colleagues and friends, I want to thank Orla (that also worked in Birmngham), Laura and Michelle for being part the great team that cheers me up inside and outside the lab. Thanks to Silvia, Piergiorgio, Leigh, Lee, Prof. Roberto Pili, Jason, Sara and Connor for the friendship and the support! Thanks also my great room mate Kelly for the awesome help she gave me as soon as I arrived and for the many headaches on Saturday mornings; thanks to all the guys I met here and helped me feeling like home: Andy, George, Mike, Jet, Mary, Amy, Alex and Jessie. Thanks to all the fella ESRs, every meeting/course/conference was fantastic and memorable also thanks to the environment that we all created. Undoubtedly the biggest support ever came from my family, my mum Marina, my dad Marcello and my awesome sister Cristina. They never stopped believing in me and even if I was always far away they have always been really close!! Thanks!! 7 List of Abbreviations LIST OF ABBREVIATIONS 1α,25(OH)2D3 1alpha,25-dihydroxy-vitamin D3 ABC ATP-binding cassette AF-1 activation function 1 AF-2 activation function 2 AIB1 amplified in breast cancer 1 ALOX5 arachidonate-5-lypoxigenase AMACR α-methylacyl-CoA racemase AMP adenosine monophosphate AMV avian myeloblastosis ANOVA analysis of variance AP1/2 activator protein 1/2 APAF1 apoptotic protease-activating factor 1 APC adenopolyposis coli APL acute promyelocytic leukaemia
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