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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 488-496 |
| Number of pages | 9 |
| Journal | Nature Medicine |
| Volume | 22 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2016 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Medicine(all)
Cite this
ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer. / Wang, Junjian; Zou, June X; Xue, Xiaoqian; Cai, Demin; Zhang, Yan; Duan, Zhijian; Xiang, Qiuping; Yang, Joy C.; Louie, Maggie C.; Borowsky, Alexander D; Gao, Allen C; Evans, Christopher P; Lam, Kit; Xu, Jianzhen; Kung, Hsing-Jien; Evans, Ronald M.; Xu, Yong; Chen, Hongwu.
In: Nature Medicine, Vol. 22, No. 5, 01.05.2016, p. 488-496.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ROR-γ drives androgen receptor expression and represents a therapeutic target in castration-resistant prostate cancer
AU - Wang, Junjian
AU - Zou, June X
AU - Xue, Xiaoqian
AU - Cai, Demin
AU - Zhang, Yan
AU - Duan, Zhijian
AU - Xiang, Qiuping
AU - Yang, Joy C.
AU - Louie, Maggie C.
AU - Borowsky, Alexander D
AU - Gao, Allen C
AU - Evans, Christopher P
AU - Lam, Kit
AU - Xu, Jianzhen
AU - Kung, Hsing-Jien
AU - Evans, Ronald M.
AU - Xu, Yong
AU - Chen, Hongwu
PY - 2016/5/1
Y1 - 2016/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84961878425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84961878425&partnerID=8YFLogxK
U2 - 10.1038/nm.4070
DO - 10.1038/nm.4070
M3 - Article
C2 - 27019329
AN - SCOPUS:84961878425
VL - 22
SP - 488
EP - 496
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -