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Status |
Public on Mar 08, 2016 |
Title |
ROR-γ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer |
Organism |
Homo sapiens |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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.
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Overall design |
A total of 6 samples were analyzed in this study. The study included one cell line C4-2B. C4-2B cells were cultured in medium containing vehicle control and/or SR2211 and/or XY011 and/or Enzalutamide (ENZ). The untreated C4-2B cells served as controls for the study.
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Contributor(s) |
Chen H, Wang J |
Citation(s) |
27019329 |
Submission date |
Aug 28, 2015 |
Last update date |
May 15, 2019 |
Contact name |
Junjian Wang |
E-mail(s) |
jjwang@ucdavis.edu
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Phone |
9167343221
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Organization name |
UC Davis
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Department |
Biochemistry and molecular medicine
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Street address |
rm1204, Res3, 4645 2nd Ave
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City |
Sacramento |
State/province |
california |
ZIP/Postal code |
95817 |
Country |
USA |
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Platforms (1) |
GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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Samples (6)
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Relations |
BioProject |
PRJNA294140 |
SRA |
SRP062942 |