Abstract 1046: The histone methyl transferase MMSET/WHSC1 promotes an epithelial-mesenchymal transition and invasive properties of prostate cancer

Abstract

Abstract Prostate cancer (PCa) remains the most common neoplasia diagnosed among men in the USA, and the second leading cause of cancer deaths. Recent evidence has indicated that epigenetic alterations contribute to the initiation and progression of PCa; however, the mechanisms by which chromatin modifiers influence this disease are still poorly understood. The histone methyl transferase MMSET (Multiple Myeloma Set Domain) is overexpressed in a number of different tumor types, including PCa. While the precise mechanism of MMSET action is still not well defined, it is believed to involve alteration of chromatin structure through dimethylation of lysine 36 on histone H3 (H3K36me2). Analysis of microarray databases indicates that MMSET expression rises in the progression from benign prostatic epithelium to localized and metastatic PCa. We found that PCa cell lines express significantly higher levels of MMSET compared to immortalized but non-transformed prostate cells. In t(4;14)+ myelomas, MMSET overexpression changes global levels of histone modifications, promoting H3K36me2, and repressing trimethylation of lysine 27 (H3K27me3). Similarly, H3K36me2 and H3K27me3 levels in PCa cell lines depended on the expression of MMSET, while depletion of MMSET in benign prostatic epithelial cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased soft agar colony formation and cell proliferation. Furthermore, inhibition of MMSET expression strikingly decreased cell migration and invasion, while overexpression of MMSET in immortalized non-transformed RWPE-1 cells promoted migratory and invasive properties. These findings suggest that high levels of MMSET play a pathogenic role in PCa progression. Overexpression of MMSET in RWPE-1 cells was accompanied by an epithelial to mesenchymal transition (EMT), characterized by a change in cell morphology and increased expression of mesenchymal markers vimentin and N-cadherin. Among a panel of EMT promoting genes analyzed, Twist1 expression was strongly regulated by MMSET both in the knockdown and the overexpression models. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the Twist1 locus, leading to an increase in H3K36me2 and a decrease in the repressive mark H3K27me3, suggesting a direct role of MMSET in regulation of Twist1. siRNA depletion of Twist1 in MMSET-overexpressing RWPE-1 cells blocked invasion, indicating that Twist1 was a critical target of MMSET responsible for the acquisition of EMT properties. Intriguingly, Twist1 expression was also elevated in a panel of myeloma cell lines overexpressing MMSET due to chromosomal translocation t(4;14). Collectively, these data suggest that MMSET has a critical role in cancer pathogenesis and progression through epigenetic regulation of metastasis-related genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1046. doi:1538-7445.AM2012-1046