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

SC Chan, LA Selth, Y Li, MD Nyquist… - Nucleic acids …, 2015 - academic.oup.com
SC Chan, LA Selth, Y Li, MD Nyquist, L Miao, JE Bradner, GV Raj, WD Tilley, SM Dehm
Nucleic acids research, 2015academic.oup.com
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 …
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.
Oxford University Press