Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan ; Department of Surgery, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Neoplasia. 2013 Nov;15(11):1251-61. doi: 10.1593/neo.131436.
The histone methyltransferase enhancer of zeste 2 (EZH2) is known to be a polycomb protein homologous to Drosophila enhancer of zeste and catalyzes the addition of methyl groups to histone H3 at lysine 27 (H3K27). We previously reported that EZH2 was overexpressed in various types of cancer and plays a crucial role in the cell cycle regulation of cancer cells. In the present study, we demonstrated that EZH2 has the function to monomethylate lysine 120 on histone H2B (H2BK120). EZH2-dependent H2BK120 methylation in cancer cells was confirmed with an H2BK120 methylation-specific antibody. Overexpression of EZH2 significantly attenuated the ubiquitination of H2BK120, a key posttranslational modification of histones for transcriptional regulation. Concordantly, knockdown of EZH2 increased the ubiquitination level of H2BK120, suggesting that the methylation of H2BK120 by EZH2 may competitively inhibit the ubiquitination of H2BK120. Subsequent chromatin immunoprecipitation-Seq and microarray analyses identified downstream candidate genes regulated by EZH2 through the methylation of H2BK120. This is the first report to describe a novel substrate of EZH2, H2BK120, unveiling a new aspect of EZH2 functions in human carcinogenesis.
组蛋白甲基转移酶增强子的 zeste 2（EZH2）是一种多梳蛋白，与果蝇增强子的 zeste 同源，催化组蛋白 H3 赖氨酸 27（H3K27）上甲基的添加。我们之前报道过，EZH2 在各种类型的癌症中过度表达，在癌细胞的细胞周期调控中发挥关键作用。在本研究中，我们证明了 EZH2 具有将组蛋白 H2B 赖氨酸 120 单甲基化（H2BK120）的功能。EZH2 依赖性 H2BK120 甲基化在癌细胞中得到了 H2BK120 甲基化特异性抗体的证实。EZH2 的过表达显著减弱了 H2BK120 的泛素化，这是一种关键的组蛋白转录调控的翻译后修饰。相应地，EZH2 的敲低增加了 H2BK120 的泛素化水平，这表明 EZH2 对 H2BK120 的甲基化可能竞争性地抑制 H2BK120 的泛素化。随后的染色质免疫沉淀-Seq 和微阵列分析鉴定了通过 H2BK120 甲基化由 EZH2 调控的下游候选基因。这是首次描述 EZH2 的一种新底物 H2BK120，揭示了 EZH2 在人类癌症发生中的新功能。
