Overexpression of MYC and EZH2 cooperates to epigenetically silence MST1 expression

Area of Science:

• Molecular Oncology
• Epigenetics
• Cell Signaling

Background:

• MST1 (Hippo-like protein kinase) regulates cell growth and organ size; its reduced expression correlates with poor cancer prognosis.
• The mechanisms underlying MST1 silencing in cancer, particularly prostate cancer, are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which MST1 expression is suppressed in human prostate cancer cells.
• To investigate the roles of MYC and EZH2 in MST1 gene silencing and their contribution to prostate cancer cell survival.

Main Methods:

• Quantitative reverse transcription PCR (RT-qPCR) and immunoblotting to assess gene and protein expression.
• Methylation-sensitive PCR and bisulfite genomic DNA sequencing to evaluate DNA methylation status.
• Pharmacological inhibition, RNA interference (RNAi), chromatin immunoprecipitation (ChIP) assays, and cell proliferation assays.

Main Results:

• Concurrent overexpression of MYC and EZH2 was associated with reduced MST1 expression.
• DNA methylation and EZH2-mediated H3K27me3 modification at the MST1 promoter silenced its expression, reducing H3K4me3 and RNA polymerase II occupancy.
• MYC and EZH2 inhibited MST1 promoter activity; EZH2 acted as a mediator of MYC-induced silencing, partly via microRNA-26a/b.
• Inhibitors of MYC or EZH2 suppressed prostate cancer cell growth, while MST1 knockdown conferred resistance to these inhibitors.

Conclusions:

• MYC and EZH2 epigenetically suppress MST1 expression in prostate cancer through DNA methylation and repressive histone modifications.
• The loss of MST1/Hippo pathway function is crucial for MYC/EZH2-driven cancer cell survival, highlighting a potential therapeutic vulnerability.