The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial–mesenchymal transition and invasive properties of prostate cancer

Abstract

Epigenetic deregulation of gene expression plays a role in the initiation and progression of prostate cancer (PCa). The histone methyltransferase MMSET/WHSC1 (Multiple Myeloma Set Domain) is overexpressed in a number of metastatic tumors, but its mechanism of action has not been defined. In this work, we found that PCa cell lines expressed significantly higher levels of MMSET compared to immortalized, non-transformed prostate cells. Knockdown experiments showed that, in metastatic PCa cell lines, dimethylation of lysine 36 and trimethylation of lysine 27 on histone H3 (H3K36me2 and H3K27me3, respectively) depended on MMSET expression, while depletion of MMSET in benign prostatic cells did not affect chromatin modifications. Knockdown of MMSET in DU145 and PC-3 tumor cells decreased cell proliferation, colony formation in soft agar, and strikingly diminished cell migration and invasion. Conversely, overexpression of MMSET in immortalized, non-transformed RWPE-1 cells promoted cell migration and invasion, accompanied by an epithelial to mesenchymal transition (EMT). Among a panel of EMT-promoting genes analyzed, TWIST1 expression was strongly activated in response to MMSET. Chromatin immunoprecipitation analysis demonstrated that MMSET binds to the TWIST1 locus, leading to an increase in H3K36me2, suggesting a direct role of MMSET in the regulation of this gene. Depletion of TWIST1 in MMSET-overexpressing RWPE-1 cells blocked cell invasion and EMT, indicating that TWIST1 was a critical target of MMSET, responsible for the acquisition of an invasive phenotype. Collectively, these data suggest that MMSET plays a role in PCa pathogenesis and progression through epigenetic regulation of metastasis-related genes.

Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem–like Cell Traits in Breast Cancer

“…Transcriptionally, TWIST1 can be regulated by miRNAs and transcription factors such as HMGA2, KLF17, and STAT3 (24)(25)(26)(27). Epigenetic modifications, including DNA and histone methylation, also play roles in the activation of TWIST1 expression (28,29). However, the regulation of the histone acetylation status of TWIST1 has not been reported.…”

H3K36 Methyltransferases as Cancer Drug Targets: Rationale and Perspectives for Inhibitor Development

“…In prostate cancer for example, the EZH2/NSD2 axis confers increased cell proliferation, migration, invasion, stem cell-like properties and tumor growth in a mouse xenograft model [66]. Further studies in prostate cancer have shown that NSD2 acts as a co-activator with NF-κB and androgen receptor [67,68], and regulates the epithelial to mesenchymal transition by dimethylating H3K36 at the TWIST1 locus and activating TWIST1 expression [69].NSD3: frequently overexpressed in diverse tumor types NSD3, also known as WHSC1L1, is overexpressed in cancer [70] and catalyzes mono-and di-methylation at H3K36 in vitro [71]. In cells NSD3 functions as a transcriptional activator, but NSD3's KMTase activity may contribute only partially to its geneactivating role.…”

“…In prostate cancer for example, the EZH2/NSD2 axis confers increased cell proliferation, migration, invasion, stem cell-like properties and tumor growth in a mouse xenograft model [66]. Further studies in prostate cancer have shown that NSD2 acts as a co-activator with NF-κB and androgen receptor [67,68], and regulates the epithelial to mesenchymal transition by dimethylating H3K36 at the TWIST1 locus and activating TWIST1 expression [69].…”

In vitro histone lysine methylation by NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L

“…The NSD proteins are oncogenes highly expressed in numerous pathological conditions and are considered attractive novel therapeutic targets in cancers [2,[9][10][11][12][13][14][15][16][17][18][19][20]. The amplification of NSD1 has been reported in multiple myeloma, lung cancer, neuroblastoma and glioblastoma.…”

“…Therefore, the inhibition of NSD members by small molecules represents a valuable therapeutic strategy in several human cancers where elevated levels of NSD members have been reported [2,4,5,12,14,17,18,26,32,33,[43][44][45].…”