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N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

ABSTRACT: N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

PROVIDER: PRJNA481735 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7536830.fastq.gz	Fastqsanger.gz
	SRR7536840.fastq.gz	Fastqsanger.gz
	SRR7536850.fastq.gz	Fastqsanger.gz
	SRR7536900_1.fastq.gz	Fastqsanger.gz
	SRR7536900_2.fastq.gz	Fastqsanger.gz

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Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.

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