2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Cellular and Molecular Immunology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.
Cell Rep. 2019 Nov 5;29(6):1482-1498.e4. doi: 10.1016/j.celrep.2019.10.004.
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.
增强子结合锌指蛋白 2（EZH2）是一种组蛋白 H3 赖氨酸 27 三甲基化的主要转录调控因子。我们旨在阐明 EZH2 的精确翻译后调控及其在癌症发病机制中的作用。在这里，我们表明 SET 和 MYND 结构域包含 2（SMYD2）直接在赖氨酸 307（K307）处甲基化 EZH2，并增强其稳定性，该稳定性可以被组蛋白 H3K4 去甲基化酶赖氨酸特异性去甲基酶 1（LSD1）解除。SMYD2 对于 EZH2 抑制一组控制多种癌症相关途径的基因的功能至关重要。此外，SMYD2 通过 EZH2 K307 甲基化促进乳腺癌细胞增殖、上皮-间充质转化和侵袭，并且在各种人类癌症中显著上调。我们的数据表明，SMYD2 介导的 EZH2 甲基化之间的动态串扰在精细调节 EZH2 在染色质募集和转录抑制中的功能方面起着重要作用。
