Key Laboratory of Molecular Epigenetics of the Ministry of Education, Northeast Normal University, Changchun, Jilin 130024, P.R. China.
Department of Toxicology, Jilin Province Institution of Tumor Research, Changchun, Jilin 130000, P.R. China.
Oncol Rep. 2018 Nov;40(5):3069-3077. doi: 10.3892/or.2018.6669. Epub 2018 Aug 23.
Accumulating evidence has revealed that the methylation of lysines on nonhistones by histone lysine methyltransferases (HMTs) is crucial for regulating tumo-rigenesis and metastasis. However, whether the methy-lation of lysines on HMT complex components occurs and has functions in cancer progression is less well understood. WD repeat domain 5 (WDR5) is a core component of an HMT complex named mixed lineage leukemia (MLL)/Suppressor of Variegation, Enhancer of Zeste, and Trithorax 1 (SET1). In the present study, it was reported that lysines 207 and 325 (K207 and K325, respectively) of WDR5 were monomethylated by SET‑domain‑containing protein methyltransferase 6. Disrupting the methylation of K207/K325 via a K207R/K325R double‑site mutation attenuated the WDR5 promotion of breast cancer cell proliferation and migration. Methylation of K207/K325 on WDR5 partially contributed to maintaining global histone tri‑methylation of lysine 4 on histone H3 levels, but did not affect MLL/SET1 complex assembly. These results further understanding of a potential post‑translational modification of WDR5, and imply that the methylation of lysines on HMT complex components is crucial for regulating human carcinogenesis.
越来越多的证据表明，组蛋白赖氨酸甲基转移酶（HMTs）对非组蛋白赖氨酸的甲基化在调节肿瘤发生和转移中至关重要。然而，HMT 复合物组成成分赖氨酸的甲基化是否发生以及在癌症进展中是否具有功能还不太清楚。WD 重复结构域 5（WDR5）是一种名为混合谱系白血病（MLL）/变异性增强抑制因子、增强子结合锌指蛋白 1（SET1）的 HMT 复合物的核心组成部分。在本研究中，据报道，WDR5 的赖氨酸 207 和 325（分别为 K207 和 K325）被 SET 结构域包含的蛋白质甲基转移酶 6 单甲基化。通过 K207R/K325R 双位点突变破坏 K207/K325 的甲基化，减弱了 WDR5 促进乳腺癌细胞增殖和迁移的作用。WDR5 上 K207/K325 的甲基化部分有助于维持组蛋白 H3 赖氨酸 4 的全局三甲基化水平，但不影响 MLL/SET1 复合物的组装。这些结果进一步了解了 WDR5 的一种潜在的翻译后修饰，暗示 HMT 复合物组成成分赖氨酸的甲基化在调节人类致癌作用中至关重要。
