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The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44319 | GEO | 2013/02/15

SECONDARY ACCESSION(S): PRJNA189455

REPOSITORIES: GEO

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The E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity cancer.

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).

2013-02-15 | E-GEOD-44319 | biostudies-arrayexpress

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: kinetic analysis after DHT treatment

Project description:Androgen receptor (AR) signaling remains the key therapeutic target in the management of hormone-naïve advanced prostate cancer (PCa) and castration-resistant PCa (CRPC). Recently, landmark molecular features have been reported for CRPC, including the expression of constitutively active AR variants that lack the ligand-binding domain. Besides their role in CRPC, AR variants lead to the expression of genes involved in tumor progression. However, little is known about the specificity of their mode of action compared with that of wild-type AR (AR-WT). We performed AR transcriptome analyses in an androgen-dependent PCa cell line as well as cross-analyses with publicly available RNA-seq dataset and established that transcriptional repression capacity that was marked for AR-WT was pathologically lost by AR variants. Functional enrichment analyses allowed us to associate AR-WT repressive function to a panel of genes involved in cell adhesion and epithelial-to-mesenchymal transition. So, we postulate that a less documented AR-WT normal function in prostate epithelial cells could be the repression of a panel of genes linked to cell plasticity, and that this repressive function could be pathologically abrogated by AR variants in PCA.

2022-10-13 | PXD029520 | Pride

Transcriptional repression activity of androgen receptor targets cell plasticity in prostate cancer: BioID analysis

2022-10-14 | PXD029454 | 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

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 1)

Project description:Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.

2022-04-06 | PXD021428 | Pride

Schlafen family member 5 (SLFN5) regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer (PART 2)

2022-10-14 | PXD021405 | Pride

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.

2016-03-08 | E-GEOD-72483 | biostudies-arrayexpress

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ChIP-seq]

Project description:Castration resistant prostate cancers (CRPCs) lose sensitivity to androgen deprivation therapies but frequently remain dependent on oncogenic transcription driven by androgen receptor (AR) and its splice variants. To discover novel modulators of AR variant activity, we used a lysate-based small molecule microarray (SMM) assay and identified KI-ARv-03 as an AR variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742 , an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo , oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.

2020-10-05 | GSE156882 | GEO

Modulating Androgen Receptor-driven Transcription in Prostate Cancer with Selective CDK9 Inhibitors [ATAC-seq]

2020-10-05 | GSE156881 | GEO

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