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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. Gene expression profiling of LP50 cells showed that AR regulates two largely distinct gene expression programs, androgen-dependent and apo-AR dependent. Furthermore, a DNA binding domain mutant of AR which is unable to bind to ARE rescued androgen depletion insensitive proliferation and gene activation in LP50 cells iii depleted of endogenous wild type AR. Furthermore, ChIP-chip promoter tiling arrays revealed enrichment for AR in chromatin sites that are functional but lack ARE. To identify candidate transcription factors that tether AR to target genes in the absence of androgen, cis-elements of transcription factors in the AR interactome data set and AR chip peaks were used. We found direct interaction between AR and Elk-1 in both the C81 and C4-2 LNCaP variants of androgen depletion insensitive experimental model systems representing clinical advanced prostate cancer. AR dependent promoter activity of an Elk-1 driven promoter reporter construct and physical association between AR and Elk-1 by coimmunoprecipitation suggested that AR acts as a co-activator of Elk-1. Elk-1 was shown to be necessary for the proliferation of C81 and C4-2 cells. Expression profile studies further showed AR-dependent activation of gene clusters enriched for cell division function by Elk-1. This AR dependent gene regulation by Elk-1 was insensitive to androgen antagonist. The present study suggests that in advanced prostate cancer AR can support the progression of the tumor through ARE independent mechanisms by acting as a transcriptional co-activator for transcription factors such as Elk-1. This mechanism of action of AR is insensitive to hormone as well as antiandrogen. Hence, therapeutic strategies selectively targeting the interactions between AR and critical tethering proteins could be a novel approach for the management of advanced prostate cancer. iv Acknowledgements First and for most I would like to express my sincere gratitude to my major advisor Dr. Manohar Ratnam for his wonderful mentorship, guidance and generous support for my study. I am very grateful to my graduate research advisory committee members: Dr. Lirim Shemshedini, Dr. Robert Trumbly, Dr. Beata Lecka-Czernik and Dr. Edwin Sanchez whose advice, suggestions and continuous help have been invaluable. Special thanks should be given to Dr. Randall Ruch who helped me in many ways. I would like to thank former and current laboratory members: Dr. Juan Zhang, Dr Aymen Shatnawi, Dr. Marcela d'Alincourt Salazar, Suneethi Sivakumaran, Theodore Manolukas, Venkatesh Chari and Mugdha Patki for their contribution for this work and creating collegial work environment. Last but not least, I would like to express my deepest gratitude for my parents who put the greatest trust and confidence in me all the time. v Table of content Abstract .............................................................................................................................. iii Acknowledgements ............................................................................................................. v Table of content ................................................................................................................. vi Chapter 1: Introduction and Literature review .................................................................. 1 Introduction ..................................................................................................................... 1 Literature review ............................................................................................................. 9 Chapter 2: Hormone Depletion-Insensitivity of Prostate Cancer Cells is Supported by the Androgen Receptor without Binding to Classical Response Elements ...................... 47 Abstract ......................................................................................................................... 48 Introduction ................................................................................................................... 49 Results ........................................................................................................................... 52 Discussion ..................................................................................................................... 61 Materials and Methods .................................................................................................. 66 References ..................................................................................................................... 76 Figure Legends and Figures .......................................................................................... 82 vi Chapter 3: Elk-1 Recruits the Androgen Receptor as a Coactivator and is Necessary for Androgen Receptor Dependent Growth of Advanced Prostate Cancer Cells ................... 97 Abstract ......................................................................................................................... 98 Introduction ................................................................................................................... 99 Materials and methods ................................................................................................ 101 Results ......................................................................................................................... 108 Discussion ................................................................................................................... 114 References ................................................................................................................... 119 Figure Legends and Figures ........................................................................................ 124 Chapter 4: Summary and Conclusion ........................................................................... 135 References ....................................................................................................................... 142 A: SUPPLEMENT 1....................................................................................................... 170 B: SUPPLEMENT 2 ....................................................................................................... 213 C: SUPPLEMENT 3....................................................................................................... 216 D: SUPPLEMENT 4....................................................................................................... 220 vii Chapter 1 Introduction and Literature review Introduction Androgens regulate a variety of physiological functions and exert their genotropic action through the androgen receptor (AR). The androgen receptor plays a pivotal role in reproduction, gender differentiation, development of muscle mass and bone strength. AR is required for development, maintenance and function of the prostate (1). In addition to its normal physiological roles, AR is also involved in the development of prostatic hyperplasia and malignancy and is expressed in most hormone refractory prostate tumors (2, 3). In the United States, prostate cancer is the second leading cause of cancer death in men. In 2010 an estimated 217, 730 new cases were reported and about 32,050 men died of prostate cancer the same year. The high incidence of prostate cancer is attributed to an increase in the aging population, early detection due to the increase in the number of men undergoing screening and improved health care service (4). 1 The remarkable sensitivity of prostatic epithelial cells to androgens has been known for a while, and tapped in the management of prostate cancer. To date, androgen ablation therapy is the mainstay for the treatment of advanced prostate cancer (2). Hormone ablation therapy initially yields
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