Title |
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer
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Published in |
Nature Medicine, March 2016
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DOI | 10.1038/nm.4070 |
Pubmed ID | |
Authors |
Junjian Wang, June X Zou, Xiaoqian Xue, Demin Cai, Yan Zhang, Zhijian Duan, Qiuping Xiang, Joy C Yang, Maggie C Louie, Alexander D Borowsky, Allen C Gao, Christopher P Evans, Kit S Lam, Jianzhen Xu, Hsing-Jien Kung, Ronald M Evans, Yong Xu, Hong-Wu Chen |
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 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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 5 | 42% |
United Kingdom | 1 | 8% |
Saudi Arabia | 1 | 8% |
New Zealand | 1 | 8% |
Peru | 1 | 8% |
Unknown | 3 | 25% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 6 | 50% |
Scientists | 3 | 25% |
Practitioners (doctors, other healthcare professionals) | 2 | 17% |
Science communicators (journalists, bloggers, editors) | 1 | 8% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Korea, Republic of | 1 | <1% |
Uruguay | 1 | <1% |
Finland | 1 | <1% |
Denmark | 1 | <1% |
Japan | 1 | <1% |
Unknown | 160 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 33 | 20% |
Student > Ph. D. Student | 29 | 18% |
Student > Bachelor | 16 | 10% |
Student > Master | 13 | 8% |
Other | 10 | 6% |
Other | 31 | 19% |
Unknown | 33 | 20% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 34 | 21% |
Agricultural and Biological Sciences | 31 | 19% |
Medicine and Dentistry | 30 | 18% |
Chemistry | 8 | 5% |
Pharmacology, Toxicology and Pharmaceutical Science | 7 | 4% |
Other | 14 | 8% |
Unknown | 41 | 25% |