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ROR-Î³ 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 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Junjian Wang

PROVIDER: E-GEOD-72483 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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-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.

2016-03-08 | GSE72714 | GEO

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.

2016-03-08 | GSE72483 | GEO

ChIP-sequencing of prostate cancer cells

Project description:Chromatin from LNCaP-C4-2B cells was immunoprecipitated using pY88-H4 or IgG antibodies, followed by sequencing of the ChIP-DNA Examination of the distribution of pY88-H4 epigenetic marks in CRPC cell line

2016-03-29 | E-GEOD-79658 | biostudies-arrayexpress

SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer

Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 24 LuCaP PCa xenograft lines and 71 CRPC metastases from 47 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.

2015-06-24 | E-GEOD-66187 | biostudies-arrayexpress

Activation of the P-TEFb Complex by Lethal Prostate Cancer-Associated Enhancer RNAs [ChIP-Seq]

Project description:Castration resistant prostate cancer (CRPC) is a lethal disease1-4. Aberrant activation of the androgen receptor (AR) becomes a central mechanism contributing to the resistance of endocrine therapies2,3. Here we demonstrate that non-coding RNAs transcribed from the AR bound-enhancers RNAs (AR-eRNAs) are upregulated in human CRPC cells in vitro, xenografts in vivo and patient tissues. Expression of a subset of genes with elevated AR-eRNAs, including TLE1 and HTR3A, is inversely correlated with biochemical recurrence-free survival of CRPC patients. We identify aan HIV-1 TAR-like (TAR-L) motif in AR-eRNAs of AR target genes including KLK3 (or PSA) and TMPRSS2. The TAR-L motif is important for these eRNAs to bind to CYCLIN T1 of the positive transcription elongation factor b (P-TEFb) complex. Knockdown of PSA eRNA diminishes RNA polymerase II (Pol II) serine-2 (Ser-2) phosphorylation at the PSA promoter. The TAR-L motif in KLK3 eRNA is crucial for effective transcription of PSA mRNA. Together, wWe demonstrate a P-TEFb activation function of eRNA and reveal aberrant eRNA expression as a functional indicator of AR abnormality in CRPC. Our results also suggest that eRNAs as amay be a potential target for CRPC therapy. Androgen receptor (AR) binding sites in human prostate cancer cell lines, LNCaP and C4-2, were studied using ChIP-seq. ChIP enriched and input DNA were sequenced using Illumina HiSeq 2000.

2016-02-12 | E-GEOD-55031 | biostudies-arrayexpress

The androgen receptor induces a distinct transcriptional program in castration resistant prostate cancer in man

Project description:The androgen receptor (AR) is the major transcriptional driver of prostate cell growth in man. For the first time, we define AR targets in prostate cancer (PC) tissue representing progression from treatment-naive to castrate-resistant disease (CRPC). We employed chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies. We uncovered an AR transcriptional network not observed in cultured cells, with significant over-representation of MYC, E2F and STAT binding sites, progenitor cell gene signatures and targets which regulate metabolism, cell cycle and steroid biosynthesis. We identified AR targets unique to CRPC tissue, with a subset over-expressed in CRPC and predictive of clinical outcome, highlighting persistence of AR signalling. Our data support a model whereby endocrine and paracrine signals converge on the AR in PC tissue to drive oncogenic transcriptional programs, highlighting the critical role of cellular context in the regulation of target selection and gene expression. chromatin immunoprecipitation with high through-put sequencing (ChIP-seq) in human tissue, with cell-line and xenograft studies

2013-01-04 | E-GEOD-28219 | biostudies-arrayexpress

Characterization of AR interactome in prostate cancer cells after MC3324 treatment

Project description:We here investigated the alterations in the androgen receptor (AR) itneractome after treatment with the dual-KDM inhibitor MC3324.

2022-10-13 | PXD029249 | Pride

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

The ETS family member GABPa mediates the development of castrate-resistant prostate cancer (ChIP-Seq)

Project description:In prostate cancer, the androgen receptor (AR) is a key transcription factor at all disease stages. We recently showed that during progression to castrate-resistant prostate cancer the AR acquires the ability to bind to a distinct set of genomic sites in tissue samples and that some of the genes that are regulated by the AR in these conditions correlate with poor prognosis. Based on this work we hypothesised that the AR is reprogrammed through interactions with other transcription factors. In the present study we show that GABPÃ¡, an ETS transcription factor which is upregulated in CRPC, is an AR-interacting transcription factor. Ectopic expression of GABPA in prostate cancer cell-lines enables them to acquire some of the molecular and cellular characteristics of CRPC tissues as well as more aggressive growth phenotypes. VCaP prostate cancer cells and Jurkat lymphoma cells were studied for the ETS factors ERG and GABPa binding sites. Each sample was compared to its input.

2014-05-21 | E-GEOD-49091 | biostudies-arrayexpress

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