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Sunkel Dissertation 04112016A.pdf (13.96 MB)

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Looking Beyond the Androgen Receptor for Transcriptional Drivers of Prostate Cancer

Sunkel, Benjamin Douglas
http://rave.ohiolink.edu/etdc/view?acc_num=osu1460377475

Abstract Details

2016, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Prostate cancer remains one of the leading causes of cancer-related deaths in American men. Further understanding of prostate carcinogenesis therefore remains a top priority in the cancer research field, and may lead to the development of novel diagnostic and treatment tools. As androgen receptor (AR) is a crucial component in initial, androgen-dependent prostate cancer (ADPC) progression, targeting AR is the current mainstay for combatting the disease in its early stages. However, resistance to AR-targeting therapy too often develops, which results in the lethal, castration-resistant growth phase of the disease. While more potent, second-generation therapies indicated for castration-resistant prostate cancer (CRPC) treatment have reached the clinic, there is still a need to identify therapeutic targets beyond the AR-signaling axis. It is increasingly understood that AR activity occurs in concert with a diverse cohort of pioneer transcription factors and coregulators that define disease stage-specific AR transcriptional output. This effectively produces a moving target and complicates our ability to efficiently observe and disrupt AR activity. Moreover, many of these same factors define the expression of their own clinically relevant gene targets independent of AR. Improving diagnostic and therapeutic success in prostate cancer requires continued focus on defining the fundamental determinants of AR function and the AR-independent transcriptional drivers of this disease. To this end, we began by defining the molecular mechanism underlying GATA2-mediated AR target gene expression in both ADPC and CRPC cells (Chapter 2). Our work supports a tripartite model of GATA2 pioneer factor activity. Firstly, we show that GATA2 supports AR expression. In AR target gene regulatory regions, GATA2 then establishes an accessible chromatin environment for AR binding. Finally, we find that GATA2 preforms regulatory chromatin loops between AR target gene enhancers and promoters. From a genome-wide perspective, these functions universally support AR genomic binding patterns, suggesting a fundamental role for GATA2 in maintaining AR activity across multiple stages of prostate cancer. We went on to conduct an integrated genomic analysis of gene expression profiles defined by the master transcription factors, CREB1 and FoxA1, in the absence of androgen (Chapter 3). These efforts establish a novel role for CREB1 in defining disease-relevant transcription profiles throughout prostate cancer progression. We further show that AR-independent FoxA1 activity involves extensive collaboration with CREB1. Genes sets collaboratively regulated by CREB1 and FoxA1 proved useful as biomarkers for predicting treatment failure among primary prostate cancer patients. Finally, we found that CREB1/FoxA1 target gene expression was sensitive to multiple kinase-inhibiting compounds. In summary, our work provides added evidence for the critical role of factors such as GATA2 in supporting AR activity throughout all stages of prostate cancer. This concept suggests that targeting AR collaborating factors could efficiently abolish genome-wide AR signaling. Finally, we define prognostic gene expression profiles regulated by the collaborative activity of CREB1 and FoxA1. These gene sets may prove effective in indicating sensitivity to future therapies that do not target AR.
Qianben Wang, PhD (Advisor)
Steven Clinton, MD/PhD (Committee Member)
Christin Burd, PhD (Committee Member)
Michael Ostrowski, PhD (Committee Member)
156 p.
Biochemistry; Biology; Molecular Biology

Recommended Citations

Citations

  • Sunkel, B. D. (2016). Looking Beyond the Androgen Receptor for Transcriptional Drivers of Prostate Cancer [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460377475

    APA Style (7th edition)

  • Sunkel, Benjamin. Looking Beyond the Androgen Receptor for Transcriptional Drivers of Prostate Cancer. 2016. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1460377475.

    MLA Style (8th edition)

  • Sunkel, Benjamin. "Looking Beyond the Androgen Receptor for Transcriptional Drivers of Prostate Cancer." Doctoral dissertation, Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1460377475

    Chicago Manual of Style (17th edition)

osu1460377475
654
© 2016, some rights reserved.Creative Commons License Looking Beyond the Androgen Receptor for Transcriptional Drivers of Prostate Cancer by Benjamin Douglas Sunkel is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.