KMT2D promotes castration-resistant prostate cancer progerssion by reactivating AR via FOXA1 [RNA-Seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1205655 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31870700_1.fastq.gz | Fastqsanger.gz | |||
| SRR31870700_2.fastq.gz | Fastqsanger.gz | |||
| SRR31870701_1.fastq.gz | Fastqsanger.gz | |||
| SRR31870701_2.fastq.gz | Fastqsanger.gz | |||
| SRR31870702_1.fastq.gz | Fastqsanger.gz |
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Project description:Histone methyltransferase KMT2D is epigenetic modifier mediates histone H3 lysine 4 methylation (H3K4me) with distinct roles across different cancer types. We previous found that KMT2D promotes growth and metastasis in Androgen receptor (AR)-negative prostate cancer (PCa). However, the functions of KMT2D and the relationship with AR in AR-positive prostate cancer remain unclear. Here, we showed that inhibition of KMT2D reduced AR-positive PCa cell survival and the sensitivity to dihydrotestosterone, a ligand for AR. RNA-Seq analysis revealed that KMT2D suppression significantly attenuated AR signaling pathway. Through multiple-omics analysis, we revealed that KMT2D recruits pioneering transcription factor Forkhead box A1 (FOXA1) to AR-specific enhancer sites, induces open chromatin conformations, and facilitates AR binding at enhancers to activate downstream gene expression, ultimately leading to AR reactivation. KMT2D knockout by CRISPR/Cas9 reduced CRPC tumor growth and AR signaling pathway activation in vivo. KMT2D-FOXA1-AR axis also mediates ketone metabolic reprogramming by regulating the expression of the key enzyme HMGCS2 to promote PCa progression. Finally, targeting UTX, a member of complex of proteins associated with SET1 (COMPASS) in which KMT2D involved, suppressed PCa cell survival and tumor growth by impairing H3K4me1 modification via KMT2D. These findings demonstrate the oncogenic role of KMT2D in PCa, suggesting that blocking COMPASS to inhibition KMT2D’s function may be a promising strategy to treat PCa.
2025-02-01 | GSE285692 | GEO
Project description:Histone methyltransferase KMT2D is epigenetic modifier mediates histone H3 lysine 4 methylation (H3K4me) with distinct roles across different cancer types. We previous found that KMT2D promotes growth and metastasis in Androgen receptor (AR)-negative prostate cancer (PCa). However, the functions of KMT2D and the relationship with AR in AR-positive prostate cancer remain unclear. Here, we showed that inhibition of KMT2D reduced AR-positive PCa cell survival and the sensitivity to dihydrotestosterone, a ligand for AR. RNA-Seq analysis revealed that KMT2D suppression significantly attenuated AR signaling pathway. Through multiple-omics analysis, we revealed that KMT2D recruits pioneering transcription factor Forkhead box A1 (FOXA1) to AR-specific enhancer sites, induces open chromatin conformations, and facilitates AR binding at enhancers to activate downstream gene expression, ultimately leading to AR reactivation. KMT2D knockout by CRISPR/Cas9 reduced CRPC tumor growth and AR signaling pathway activation in vivo. KMT2D-FOXA1-AR axis also mediates ketone metabolic reprogramming by regulating the expression of the key enzyme HMGCS2 to promote PCa progression. Finally, targeting UTX, a member of complex of proteins associated with SET1 (COMPASS) in which KMT2D involved, suppressed PCa cell survival and tumor growth by impairing H3K4me1 modification via KMT2D. These findings demonstrate the oncogenic role of KMT2D in PCa, suggesting that blocking COMPASS to inhibition KMT2D’s function may be a promising strategy to treat PCa.
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Project description:Histone methyltransferase KMT2D is epigenetic modifier mediates histone H3 lysine 4 methylation (H3K4me) with distinct roles across different cancer types. We previous found that KMT2D promotes growth and metastasis in Androgen receptor (AR)-negative prostate cancer (PCa). However, the functions of KMT2D and the relationship with AR in AR-positive prostate cancer remain unclear. Here, we showed that inhibition of KMT2D reduced AR-positive PCa cell survival and the sensitivity to dihydrotestosterone, a ligand for AR. RNA-Seq analysis revealed that KMT2D suppression significantly attenuated AR signaling pathway. Through multiple-omics analysis, we revealed that KMT2D recruits pioneering transcription factor Forkhead box A1 (FOXA1) to AR-specific enhancer sites, induces open chromatin conformations, and facilitates AR binding at enhancers to activate downstream gene expression, ultimately leading to AR reactivation. KMT2D knockout by CRISPR/Cas9 reduced CRPC tumor growth and AR signaling pathway activation in vivo. KMT2D-FOXA1-AR axis also mediates ketone metabolic reprogramming by regulating the expression of the key enzyme HMGCS2 to promote PCa progression. Finally, targeting UTX, a member of complex of proteins associated with SET1 (COMPASS) in which KMT2D involved, suppressed PCa cell survival and tumor growth by impairing H3K4me1 modification via KMT2D. These findings demonstrate the oncogenic role of KMT2D in PCa, suggesting that blocking COMPASS to inhibition KMT2D’s function may be a promising strategy to treat PCa.
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Project description:KMT2D promotes castration-resistant prostate cancer progerssion by reactivating AR via FOXA1 [ATAC-Seq]
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Project description:KMT2D promotes castration-resistant prostate cancer progerssion by reactivating AR via FOXA1 [ChIP-seq, Cut & Tag]
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2025-11-19 | PXD070903 | Pride
Project description:BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of various malignancies. However, its role in prostate cancer (PCa) remains poorly understood. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily upregulates the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF facilitates AR binding to enhancers and super-enhancers, while ATAC-seq demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, partly via SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR shared ChIP-seq peaks are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We find that BPTF interacts with both FOXA1 and AR to form a protein complex in which FOXA1 recruits BPTF-AR 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, leading to impaired AR signaling and suppressed 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.
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Project description:Targeted disruption of the embryonic stem cell (ESC) self-renewal and pluripotency factor NANOG diminishes cancer cell clonogenic growth in vitro and tumor development in vivo. NANOG has also been shown to augment CSC properties and propel the emergence of castration-resistance prostate cancer (CRPC) phenotypes. Here, we investigate the molecular mechanisms underlying NANOG-mediated oncogenesis and prostate cancer progression to androgen independence. ChIP-Seq analysis of LNCaP prostate cancer cells overexpressing doxycycline-inducible NANOG (either NANOG1 or NANOGP8 vs pLVX control) reveal that NANOG coordinately occupies regions of chromatin regulated by AR signaling steroid-receptor complex proteins AR, FOXA1 and NKX3.1. Taken together with the NANOG-induced changes in the prostate cancer transcriptome (RNA-Seq), NANOG appears to reprogram prostate cancer cells to castration resistance by converging on steroid-hormone receptor signaling.
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Project description:BPTF, the scaffolding subunit of the nucleosome remodeling factor (NURF) complex, has been implicated in the progression of various malignancies. However, its role in prostate cancer (PCa) remains poorly understood. Here, we demonstrate that BPTF is upregulated in castration-resistant prostate cancer (CRPC) and promotes disease progression. RNA-seq revealed that BPTF primarily upregulates the expression of androgen receptor (AR) target genes. ChIP-seq showed that BPTF facilitates AR binding to enhancers and super-enhancers, while ATAC-seq demonstrated that BPTF increases chromatin accessibility to facilitate AR binding, partly via SMARCA1, a catalytic subunit of the NURF complex. Notably, BPTF/AR shared ChIP-seq peaks are highly enriched for FOXA1 motifs but only weakly enriched for AR motifs. We find that BPTF interacts with both FOXA1 and AR to form a protein complex in which FOXA1 recruits BPTF-AR 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, leading to impaired AR signaling and suppressed 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.
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