ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancerNature Medicine (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 retinoic 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 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-γ antagonists suppress the expression of both 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 target gene network. Finally, ROR-γ 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-γ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa.
- castration-resistant prostate cancer
Publication DateMay, 2016
Citation InformationJujian Wang, June X. Zou, Xiaoqian Xue, Demin Cai, et al.. "ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer" Nature Medicine Vol. 22 Iss. 5 (2016) p. 488 - 496 ISSN: 1078-8956
Available at: http://works.bepress.com/maggie_louie/30/