Junjian Wang 1 , June X. Zou 1 , Xiaoqian Xue 2 , Demin Cai 1 , Yan Zhang 2 , Zhijian Duan 1 , Qiuping Xiang 2 , Joy C. Yang 3 , Maggie C. Louie 4 , Alexander D. Borowsky 5 , Allen C. Gao 3 , 8 , Christopher P. Evans 3 , 8 , Kit S. Lam 1 , 8 , Jianzhen Xu 6 , Hsing-Jien Kung 1 , 8 , Ronald M. Evans 7 , Yong Xu 2 , Hong-Wu Chen 1 , 8
28 March 2016
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 retinoid acid receptor-related orphan receptor γ (ROR-γ) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-γ drives AR expression in the tumors. ROR-γ recruits coactivators SRC-1 and -3 to an AR-RORE to stimulate AR gene transcription. ROR-γ antagonists suppress the expression of AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-γ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR gene network. Lastly, ROR-γ antagonists suppressed tumor growth in multiple AR-expressing but not AR-negative xenograft PCa models, and effectively sensitized CRPC tumors to enzalutamide, without overt toxicity in mice. Together, these results establish ROR-γ as a key player in CRPC by acting upstream of AR and a potential therapeutic target for advanced PCa.