中国学者发现促进乳腺癌生长转移关键
组蛋白赖氨酸甲基转移酶EZH2是参与组蛋白H3赖氨酸27三甲基化的主要转录调节因子，最终参与抑制基因染质转录。EZH2突变或过表达与乳腺癌等多种癌症相关，可对抑癌基因产生抑制作用，不过具体机制尚不明确
2019年11月5日，美国《细胞》旗下《细胞报告》发表天津医科大学、中国医学科学院北京协和医学院附属肿瘤医院国家癌症中心国家肿瘤临床医学研究中心、首都医科大学、温州医科大学的研究报告，探讨了EZH2转译后的精准调控机制及其对癌症发生的作用。
该研究发现，赖氨酸甲基转移酶SMYD2可以直接对EZH2的第307位赖氨酸进行甲基化并增强其稳定性，并可被组蛋白H3K4脱甲基酶赖氨酸特异脱甲基酶LSD1抑制。SMYD2对于EZH2功能对于抑制一组支配若干癌症相关通路的基因至关重要。此外，SMYD2通过对EZH2第307位赖氨酸进行甲基化，可以促进乳腺癌细胞繁殖、上皮 → 间质转化以及浸润，并且其表达水平显著提高于各种人类癌症。
因此，该研究结果表明，SMYD2及其所致EZH2甲基化之间的动态互相影响，对于调控EZH
2聚集染质和抑制转录的功能具有重要作用，可以促进乳腺癌的肿瘤生长和转移，有望成为新的靶点。
Cell Rep. 2019 Nov 5;29(6):1482-1498,e4.
Regulation of EZH2 by SMYD2-Mediated Lysine Methylation Is Implicated in Tumorigenesis.
Yi Zeng, Rongfang Qiu, Yang Yang, Tianyang Gao, Yu Zheng, Wei Huang, Jie Gao, Kai Zhang, Ruiqiong Liu, Shuang Wang, Yongqiang Hou, Wenqian Yu, Shuai Leng, Dandan Feng, Wei Liu, Xi Zhang, Yan Wang.
Tianjin Medical University, Tianjin, China; National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Capital Medical University, Beijing, China; Wenzhou Medical University, Wenzhou, Zhejiang, China.
HIGHLIGHTS
∙EZH2 is methylated by SMYD2 and is demethylated by LSD1 on lysine (K) 307
proliferation
∙EZH2 K307 methylation enhances the protein stability of EZH2
∙SMYD2 and EZH2 collaboratively participate in transcriptional repression
∙SMYD2 coordinates EZH2 to promote breast cancer tumorigenesis and metastasis
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.
KEYWORDS: methylation; tumorigenesis; breast cancer; EZH2; SMYD2; post-translational modification
DOI: 10.lrep.2019.10.004

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