Analysis of AR Gene Rearrangements in Prostate Cancer
Ontology highlight
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:BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of several malignancies, but its role in prostate cancer (PCa) remains unclear. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily enhances the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF increases AR binding at promoters, enhancers and super-enhancers. ATAC-seq further demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, in part through SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR co-bound regions are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We further show that BPTF forms a protein complex with AR and FOXA1, in which FOXA1 recruits the BPTF-AR complex to chromatin, while BPTF stabilizes the AR-FOXA1 interaction. Importantly, BPTF interacts with AR through its bromodomain, and a BPTF bromodomain inhibitor disrupts this interaction, impairs AR signaling and suppresses PCa cell growth. In summary, our findings establish BPTF as a critical regulator of AR activity by promoting chromatin accessibility and stabilizing the AR-FOXA1 complex, highlighting BPTF as a potential therapeutic target in prostate cancer.
2025-11-19 | PXD070903 | Pride
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:We investigated the role of AR in castration-resistant prostate cancer cells using AR siRNA.
2025-03-15 | GSE147219 | GEO
Project description:Androgen receptor (AR) signaling is a primary oncogenic driver of castration-resistant prostate cancer (CRPC), yet the mechanism remains incompletely understood. Dysregulation of the AR co-regulatory network has emerged as a key driver of castration resistance. To identify AR-interacting proteins linked to CRPC progression, we performed proteomics-based rapid immunoprecipitation of endogenous proteins (RIME) analysis targeting AR in the CRPC cell line C4-2B.
2026-06-08 | PXD067138 | Pride