ROR-? drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer.

ABSTRACT: The androgen receptor (AR) is overexpressed and hyperactivated in human castration-resistant prostate cancer (CRPC). However, the determinants of AR overexpression in CRPC are poorly defined. Here we show that retinoic acid receptor-related orphan receptor ? (ROR-?) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-? drives AR expression in the tumors. ROR-? recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an AR-ROR response element (RORE) to stimulate AR gene transcription. ROR-? antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-? antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-? antagonists suppressed tumor growth in multiple AR-expressing, but not AR-negative, xenograft PCa models, and they effectively sensitized CRPC tumors to enzalutamide, without overt toxicity, in mice. Taken together, these results establish ROR-? as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.

SUBMITTER: Wang J 

PROVIDER: S-EPMC5030109 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature