Abstract 1377: Transcriptional silencing of MST1/Hippo by a coordinated MYC and EZH2 signaling in prostate cancer

Abstract

Abstract Prostate cancer is a major cause of cancer-related death in western countries because of the poorly understood disease mechanisms. Hippo-like MST1 protein kinase regulates cell growth, stem cell self-renewal and carcinogenesis. The loss of Mst1 expression is implicated in the etiology several types of cancers with poor prognosis, including prostate cancer. However, the underlying mechanism of Mst1 transcriptional downregulation in prostate cancer is unknown. Here, we report that MYC and EZH2 function as epigenetic suppressors of MST1 in human prostate cancer cells. We showed that decline in MST1 expression correlated with EZH2 and MYC upregulation as demonstrated by reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) and western blot. Using methylation sensitive PCR and bisulfite genomic DNA sequencing, we showed that Mst1 promoter DNA was methylated at CpG sites that led to a reduction in MST1 expression. Our pharmacologic or RNAi experiments revealed that EZH2 contributed to MST1 silencing by inducing MST1 promoter DNA methylation and H3K27me3 modification that was accompanied by a reduced H3K4me3 mark and RNA polymerase II occupancy on MST1 promoter and thereby reducing its promoter activity and expression. On the other hand, overexpression of MYC stimulated EZH2 and conversely reduced MST1 promoter activation and its mRNA levels. Potent EZH2 inhibitors reversed the MYC effects on MST1, indicating that MYC attenuates MST1 through EZH2. Moreover, MST1 knockdown caused cell resistance to androgen deficiency and to EZH2, or MYC inhibitor-induced growth retardation. These findings indicate that MYC cooperates with EZH2 to epigenetically silence MST1 and suggest that the loss of MST1/Hippo is critical for MYC- and EZH2-driven cancer cell survival. Citation Format: Gamze Kuser Abali, Ahmet Alptekin, Bekir Cinar. Transcriptional silencing of MST1/Hippo by a coordinated MYC and EZH2 signaling in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2014-1377