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ROR-γ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72483 | GEO | 2016/03/08

SECONDARY ACCESSION(S): PRJNA294140

REPOSITORIES: GEO

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ROR-γ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Project description: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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ROR-Î³ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Project description: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 receptorârelated orphan receptor Î³ (ROR-Î³) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-Î³ drives AR expression in the tumors. ROR-Î³ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an ARâROR response element (RORE) to stimulate AR gene transcription. ROR-Î³ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-Î³ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-Î³ 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-Î³ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. 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 ÂµM) for 24 hours, cells then were collected for ChIP seq assay

2016-03-08 | E-GEOD-72714 | biostudies-arrayexpress

ROR-Î³ drives androgen-receptor expression and represents a therapeutic target in castration-resistant prostate cancer

Project description: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 receptorârelated orphan receptor Î³ (ROR-Î³) is overexpressed and amplified in metastatic CRPC tumors, and that ROR-Î³ drives AR expression in the tumors. ROR-Î³ recruits nuclear receptor coactivator 1 and 3 (NCOA1 and NCOA3, also known as SRC-1 and SRC-3) to an ARâROR response element (RORE) to stimulate AR gene transcription. ROR-Î³ antagonists suppress the expression of both AR and its variant AR-V7 in prostate cancer (PCa) cell lines and tumors. ROR-Î³ antagonists also markedly diminish genome-wide AR binding, H3K27ac abundance and expression of the AR target gene network. Finally, ROR-Î³ 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-Î³ as a key player in CRPC by acting upstream of AR and as a potential therapeutic target for advanced PCa. 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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Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: BioID analysis

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The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoeitin2

Project description:Castration-resistant prostate cancer (CRPC) is an incurable form of prostate cancer (PC) and a major therapeutic challenge. Here, we show that the natural compound, atraric acid (AA), inhibits besides the androgen receptor (AR) those AR-mutants that confer therapy resistance to AR-antagonists indicating a different mode of AR-antagonism. AA induces cellular senescence and inhibits intratumoral angiogenesis and CRPC tumour growth in treated xenograft mice. RNA-seq reveals an upregulated angiogenic transcriptional pathway by androgen. In line with this, conditioned medium from CRPC cells induces angiogenesis in two in vitro models using primary human endothelial cells. By employing immune arrays and mass-spec analyses, we found that androgens induced secretion of pro-angiogenic factors pinpointing to angiopoeitin2 (ANGPT2). The senescence-associated secretory phenotype revealed reduced ANGPT2 secretion by AA. Accordingly, immune-depletion of ANGPT2 or blocking ANGPT2-receptors inhibits angiogenesis. Our data propose AA as potential anti-PCa compound and ANGPT2 pathway as novel therapeutic target for CRPC.

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Project description:The androgen receptor (AR) plays a central role in the development of castration resistant prostate cancer (CRPC). Here, we demonstrate that the ubiquitin ligase Siah2 targets a select pool of NCOR1-bound, transcriptionally inactive AR for ubiquitination dependent degradation, thereby promoting the expression of ~13% of AR target genes. The Siah2 binding sites located within the AR ligand-binding domain are mutated in PCa, resulting in attenuation of Siah2-mediated regulation. Siah2 is required for growth of PCa cells under androgen-deprivation conditions in vitro and in vivo. Significantly, inhibition of Siah2 promotes PCa regression upon castration and Siah2 expression is markedly increased in human CRPCs. Collectively our findings identify a key role for Siah2 in CRPC through the selective regulation of AR transcriptional activity. Tumor Harvest. When tumor size reached approximately 1.5 cm in diameter (6-8 weeks after injection), and the serum PSA was greater than 50 ng/ml, animals were surgically castrated under methoxyfluorane anesthesia and monitored for PSA levels for several weeks. Animals were sacrificed by carbon dioxide asphyxiation when tumors were harvested at several points along the PSA curve (pre-castrate (11), regressing (6), nadir (10), recurring (6) and castration resistant (12). Tumor segments were placed in RNALater (Qiagen) and frozen immediately at -80M-BM-0C.weeks. Tumors were harvested at several points along the PSA curve. The epithelial:stromal ratio is consistent within this tumor model and varies 10% between tumors, as assessed by immunohistochemistry of cytokeratin 14 (epithelium) and vimentin (stroma).

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