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Nucleic Acids Res. 2015 Jul 13;43(12):5880-97. doi: 10.1093/nar/gkv262. Epub 2015 Apr 23.

Targeting chromatin binding regulation of constitutively active AR variants to overcome prostate cancer resistance to endocrine-based therapies.

Author information

1
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA.
2
Dame Roma Mitchell Cancer Research Laboratories and Freemasons Foundation Centre for Mens' Health, School of Medicine, The University of Adelaide, Adelaide, SA 5005, Australia.
3
Graduate Program in Molecular, Cellular, Developmental Biology and Genetics, University of Minnesota, Minneapolis, MN 55905, USA.
4
Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
6
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55905, USA Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55905, USA dehm@umn.edu.

Abstract

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 chromatin 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.

PMID:
25908785
PMCID:
PMC4499120
DOI:
10.1093/nar/gkv262
[Indexed for MEDLINE]
Free PMC Article

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