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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 |
Genome binding/occupancy profiling by high throughput sequencing
|
| 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 16 samples were analyzed in this study. The study included one cell line C4-2B. C4-2B cells were cultured in medium containing vehicle control or SR2211 (5 µM) for 24 hours, cells then were collected for ChIP seq assay
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| |
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| Contributor(s) |
Chen H, Wang J |
| Citation(s) |
27019329 |
| |
| Submission date |
Sep 04, 2015 |
| Last update date |
May 15, 2019 |
| Contact name |
Junjian Wang |
| E-mail(s) |
jjwang@ucdavis.edu
|
| Phone |
9167343221
|
| Organization name |
UC Davis
|
| Department |
Biochemistry and molecular medicine
|
| Street address |
rm1204, Res3, 4645 2nd Ave
|
| 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 (16)
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| Relations |
| BioProject |
PRJNA294735 |
| SRA |
SRP063334 |
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