Analysis of AR Gene Rearrangements in Prostate Cancer
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ABSTRACT:
PROVIDER: PRJNA345657 | ENA |
REPOSITORIES: ENA
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Project description:<p>Molecularly-targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signaling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumors. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class, and sub-clonal enrichment in tumors within and between patients. Despite this heterogeneity, one common outcome in tumors with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signaling in CRPC.</p>
| phs001223 | dbGaP
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
Project description:Analysis of AR-regulation of gene expression. The hypothesis tested in the present study was that AR influences the expression of genes that participate in important bioprocesses in prostate cancer cells, including cell cycle, DNA replication, recombination and repair. Results provide important information on AR-responsive genes that may be crucial to the cell survival and the progression of prostate cancer. Total RNA obtained from AR siRNA-transfected prostate cancer cells compared to negative control siRNA-transfected prostate cancer cells 48 h after siRNa transfection.
2013-07-28 | E-GEOD-49285 | biostudies-arrayexpress
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation.We performed ChIP-seq analysis to investigate the role of AR and histone modifications.In addition, by siRNA mediated knockdown of AR-associated factors, changes of AR-binding sites in prostate cancer cells were analyzed.. ChIP-sequence analysis of AR and its associated factors in prostate cancer cells
2015-02-08 | E-GEOD-62492 | biostudies-arrayexpress
Project description:Analysis of AR-regulation of gene expression. The hypothesis tested in the present study was that AR influences the expression of genes that participate in important bioprocesses in prostate cancer cells, including cell cycle, DNA replication, recombination and repair. Results provide important information on AR-responsive genes that may be crucial to the cell survival and the progression of prostate cancer.
2013-07-28 | GSE49285 | GEO
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation.We performed ChIP-seq analysis to investigate the role of AR and histone modifications.In addition, by siRNA mediated knockdown of AR-associated factors, changes of AR-binding sites in prostate cancer cells were analyzed..
2015-02-08 | GSE62492 | GEO
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation.We performed ChIP-seq analysis to investigate the role of AR and its associated factors such as coregulators or collaborating factors.In addition, by siRNA mediated knockdown of such factors, changes of AR-binding sites in prostate cancer cells were analyzed. ChIP-sequence analysis of AR and its associated factors in prostate cancer cells
2014-11-14 | E-GEOD-58428 | biostudies-arrayexpress
Project description:SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.
2021-11-25 | PXD029120 | Pride
Project description:Prostate cancer is the most common cancer in men and androgen receptor (AR) downstream signalings promote prostate cancer progression. Although androgen deprivation therapy is effective for treating prostate cancer, most of tumors relapsed as castration-resistant prostate cancer (CRPC). We performed ChIP-seq analysis to investigate the role of AR-associated factors and histone modifications using CRPC model cells, 22Rv1.
2019-04-01 | GSE123565 | GEO
Project description:We report the high-throughput profiling of AR binding in prostate cancer cells. Examination of AR binding in prostate cancer cell lines VCaP and VCS2
2012-02-01 | E-GEOD-32345 | biostudies-arrayexpress