Targeting p160 SRCs in prostate cancer with bufalin (1)
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE147172 | GEO | 2025/03/15
REPOSITORIES: GEO
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Project description:The p160 Steroid Receptor Coactivators SRC-1, SRC-2, and SRC-3 are critical components of the AR transcriptional complex and are frequently upregulated in prostate cancer (PC). We showed that inhibition of the SRCs via a small molecule inhibitor significantly diminishes AR signaling output, expression of CRPC-associated transcripts and proliferation of CRPC cells both in vitro and in vivo.
2025-03-15 | GSE147213 | GEO
Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC. LNCaP cells were transfected with control siRNA (3), GATA2 siRNA (3) or AR siRNA for 72 hours.
2015-01-21 | E-GEOD-63539 | biostudies-arrayexpress
Project description:The androgen receptor (AR) is a key driver of prostate cancer (PC), even in the state of castration-resistant PC (CRPC), and frequently even after treatment with second-line hormonal therapies such as abiraterone and enzalutamide. The persistence of AR activity via both ligand-dependent and ligand-independent (including constitutively active AR splice variants) mechanisms highlights the unmet need for alternative approaches to block AR signaling in CRPC. We investigated the transcription factor GATA2 as a regulator of AR signaling and a novel therapeutic target in PC. We demonstrate that GATA2 directly promotes AR expression (both full-length and splice variant), resulting in a strong positive correlation between GATA2 and AR expression in PC (cell lines and patient specimens). Conversely, GATA2 expression is repressed by androgen and AR, suggesting a negative feedback regulatory loop that, upon androgen deprivation, derepresses GATA2 to contribute to AR overexpression in CRPC. Simultaneously, GATA2 is necessary for optimal transcriptional activity of AR (both full-length and splice variant). GATA2 co-localizes with AR and FOXA1 on chromatin to enhance recruitment of steroid receptor coactivators (SRCs) and formation of the transcriptional holocomplex. In agreement with these important functions, high GATA2 expression and transcriptional activity predicted for worse clinical outcome in PC patients. A GATA2 small molecule inhibitor suppressed the expression and transcriptional function of AR (both full-length and splice variant) and exerted potent anticancer activity against PC cell lines. We propose pharmacological inhibition of GATA2 as a “first-in-field” approach to target AR expression and function and improve outcomes in CRPC.
2015-01-21 | GSE63539 | GEO
Project description:Targeting p160 SRCs in prostate cancer with bufalin (1)
| PRJNA613262 | ENA
Project description:Targeting p160 SRCs in prostate cancer with bufalin (2)
| PRJNA613448 | ENA
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
Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.
2018-05-21 | GSE95122 | GEO
Project description:Estrogen receptors alpha (ERα) converges estrogen signaling by orchestrating estrogen (E2)-dependent transcription regulation. Upon binding to the chromatin, ERα serves as a nucleation site for de novo formation of transcription enhancer complexes. Steroid receptor coactivators family proteins (SRCs, a.k.a p160) and Mediator complex are the two coregulators for ERα that directly interact with the receptors and control enhancer activity by regulating recruitment of other coregulators and transcription machinery. Lysine acetyltransferase p300/CBP is also a critical coregulator for ERα that is recruited through SRCs in stable ERα enhancer complex. ERα enhancers exhibit common enhancer features including enrichment of enhancer-specific histone modification (e.g. H3K4me1 and H3K27ac), coregulator recruitment, and active transcription. Despite of recognition of those enhancer characteristics, the order of assembly and functions and the functional relationships among enhancer features during active enhancer complex formation is not well understood. Using the time course genomics and molecular biology assays, we dissect the order of assembly and functions of ERα enhancer complex formation. We describe the mechanism of SRC-independent p300 recruitment mediated by Mediator, leading to initial partial activation of the ERα enhancer for enhance priming. Maturation of the enhancer in turn switches the p300 recruitment mechanism to an SRC-dependent manner, resulting in the maximum enhancer activity and transcription outcomes. Thus, our results illustrate the role of SRC in enhancing the activity of primed enhancers. Furthermore, we show that forced recruitment of p300 to inactive enhancers establishes active enhancer marks and induces ERα-target gene expression. Together, we demonstrate the molecular mechanisms of ERα enhancer complex formation where p300 plays a pivotal role in enhancer activation and target gene expression controlled by distinctive mechanisms through different stages of ERα enhancer complex formation.
2018-05-21 | GSE95121 | GEO
Project description:Building on the observation that metastatic, castration-resistant prostate cancer (CRPC) correlates with activation of Src-family tyrosine kinases, we showed that the expression of activated Src renders LNCaP androgen-independent. Here, we report on RNA-seq and/or AR ChIP-seq analyses of LNCaP, LNCaP[Src], VCaP, 22Rv1 cells grown in the presence or absence of 10 nM DHT for 16h, or LuCaP35.1 tumors grown in androgen-supplemented vs. castrated mice (androgen-dependent vs. castration-resistant). We identify an 11-gene Src-induced signature found only in CRPC in response to DHT, and moreover, the differentail expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival.
2016-12-14 | GSE92347 | GEO
Project description:Building on the observation that metastatic, castration-resistant prostate cancer (CRPC) correlates with activation of Src-family tyrosine kinases, we showed that the expression of activated Src renders LNCaP androgen-independent. Here, we report on RNA-seq and/or AR ChIP-seq analyses of LNCaP, LNCaP[Src], VCaP, 22Rv1 cells grown in the presence or absence of 10 nM DHT for 16h, or LuCaP35.1 tumors grown in androgen-supplemented vs. castrated mice (androgen-dependent vs. castration-resistant). We identify an 11-gene Src-induced signature found only in CRPC in response to DHT, and moreover, the differentail expression of a subset (DPP4, BCAT1, CNTNAP4, CDH3) correlates with earlier PC metastasis onset and poorer survival.
2016-12-20 | GSE92574 | GEO