Format

Send to

Choose Destination
See comment in PubMed Commons below
Epigenetics. 2014 Apr;9(4):634-43. doi: 10.4161/epi.27957. Epub 2014 Feb 27.

Overexpression of MYC and EZH2 cooperates to epigenetically silence MST1 expression.

Author information

1
Department of Medicine, Division of Hematology and Oncology; Biomedical Sciences, Division of Cancer Biology and Therapeutics; The Uro-Oncology Program; Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles, CA USA.
2
Department of Medicine, Division of Hematology and Oncology; Biomedical Sciences, Division of Cancer Biology and Therapeutics; The Uro-Oncology Program; Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles, CA USA; Department of Medicine; David Geffen School of Medicine; University of California Los Angeles; Los Angeles, CA USA.

Abstract

Hippo-like MST1 protein kinase regulates cell growth, organ size, and carcinogenesis. Reduction or loss of MST1 expression is implicated in poor cancer prognosis. However, the mechanism leading to MST1 silencing remains elusive. Here, we report that both MYC and EZH2 function as potent suppressors of MST1 expression in human prostate cancer cells. We demonstrated that concurrent overexpression of MYC and EZH2 correlated with the reduction or loss of MST1 expression, as shown by RT-qPCR and immunoblotting. Methylation sensitive PCR and bisulfite genomic DNA sequencing showed that DNA methylation caused MST1 silencing. Pharmacologic and RNAi experiments revealed that MYC and EZH2 silenced MST1 expression by inhibiting its promoter activity, and that EZH2 was a mediator of the MYC-induced silencing of MST1. In addition, MYC contributed to MST1 silencing by partly inhibiting the expression of microRNA-26a/b, a negative regulator of EZH2. As shown by ChIP assays, EZH2-induced DNA methylation and H3K27me3 modification, which was accompanied by a reduced H3K4me3 mark and RNA polymerase II occupancy on the MST1 promoter CpG region, were the underlying cause of MST1 silencing. Moreover, potent pharmacologic inhibitors of MYC or EZH2 suppressed prostate cancer cell growth in vitro, and the knockdown of MST1 caused cells' resistance to MYC and EZH2 inhibitor-induced growth retardation. These findings indicate that MYC, in concert with EZH2, epigenetically attenuates MST1 expression and suggest that the loss of MST1/Hippo functions is critical for the MYC or EZH2 mediation of cancer cell survival.

KEYWORDS:

DNA methylation; EZH2 and MST1/Hippo; H3K27me3; MYC; epigenetics

PMID:
24499724
PMCID:
PMC4121373
DOI:
10.4161/epi.27957
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Taylor & Francis Icon for PubMed Central
    Loading ...
    Support Center