KMT2D promotes castration-resistant prostate cancer progerssion by reactivating AR via FOXA1 [ChIP-seq, Cut & Tag]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1206094 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31881900_1.fastq.gz | Fastqsanger.gz | |||
| SRR31881900_2.fastq.gz | Fastqsanger.gz | |||
| SRR31881901_1.fastq.gz | Fastqsanger.gz | |||
| SRR31881901_2.fastq.gz | Fastqsanger.gz | |||
| SRR31881902_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.
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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: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 [RNA-Seq]
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