Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 12, Pages 5880-5897Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv262
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Funding
- National Institutes of Health [R01CA174777]
- American Cancer Society [RSG-12-031-01]
- U.S. Department of Defense Prostate Cancer Research Program [W81XWH-13-2-0093]
- Prostate Cancer Foundation of Australia [1012337, 1043482, 2011/0452]
- Masonic Cancer Center Phillip G. Semmer Scholarship
- Ray and Shirl Norman Cancer Research Trust
- Prostate Cancer Foundation
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Androgen receptor (AR) variants (AR-Vs) expressed in prostate cancer (PCa) lack the AR ligand binding domain (LBD) and function as constitutively active transcription factors. AR-V expression in patient tissues or circulating tumor cells is associated with resistance to AR-targeting endocrine therapies and poor outcomes. Here, we investigated the mechanisms governing chromatin binding of AR-Vs with the goal of identifying therapeutic vulnerabilities. By chromatin immunoprecipitation and sequencing (ChIP-seq) and complementary biochemical experiments, we show that AR-Vs display a binding preference for the same canonical high-affinity androgen response elements (AREs) that are preferentially engaged by AR, albeit with lower affinity. Dimerization was an absolute requirement for constitutive AR-V DNA binding and transcriptional activation. Treatment with the bromodomain and extraterminal (BET) inhibitor JQ1 resulted in inhibition of AR-V chromatin binding and impaired AR-V driven PCa cell growth in vitro and in vivo. Importantly, this was associated with a novel JQ1 action of down-regulating AR-V transcript and protein expression. Overall, this study demonstrates that AR-Vs broadly restore AR chro-matin binding events that are otherwise suppressed during endocrine therapy, and provides pre-clinical rationale for BET inhibition as a strategy for inhibiting expression and chromatin binding of AR-Vs in PCa.
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