Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis

The histone methyl transferase enhancer of zeste homolog 2 (EZH2) is a master transcriptional regulator involved in histone H3 lysine 27 trimethylation. We aimed to elucidate the precise post-translational regulations of EZH2 and their role in cancer pathogenesis. Here, we show that SET and MYND domain containing 2 (SMYD2) directly methylates EZH2 at lysine 307 (K307) and enhances its stability, which can be relieved by the histone H3K4 demethylase lysine-specific demethylase 1 (LSD1). SMYD2 is critical for EZH2 function in repressing a cohort of genes governing several cancer-associated pathways. In addition, SMYD2 promotes breast cancer cell proliferation, epithelial-mesenchymal transition, and invasion through EZH2 K307 methylation, and it is markedly upregulated in various human cancers. Our data suggest that dynamic crosstalk between SMYD2-mediated EZH2 methylation plays an important role in fine-tuning EZH2 functions in chromatin recruitment and transcriptional repression.