School of Biological Sciences, College of Science, Nanyang Technological University, Republic of Singapore.
Bioinformatics Institute, Agency for Science, Technology and Research, Biopolis, Republic of Singapore.
Oncogene. 2018 Jan 25;37(4):461-477. doi: 10.1038/onc.2017.309. Epub 2017 Oct 2.
Recently, we reported that the histone methyltransferase, EZH2, controls leukocyte migration through interaction with the cytoskeleton remodeling effector, VAV, and direct methylation of the cytoskeletal regulatory protein, Talin. However, it is unclear whether this extranuclear, epigenetic-independent function of EZH2 has a profound impact on the initiation of cellular transformation and metastasis. Here, we show that EZH2 increases Talin1 methylation and cleavage, thereby enhancing adhesion turnover and promoting accelerated tumorigenesis. This transforming capacity is abolished by targeted disruption of EZH2 interaction with VAV. Furthermore, our studies demonstrate that EZH2 in the cytoplasm is closely associated with cancer stem cell properties, and that overexpression of EZH2, a mutant EZH2 lacking its nuclear localization signal (EZH2ΔNLS), or a methyl-mimicking Talin1 mutant substantially promotes JAK2-dependent STAT3 activation and cellular transformation. Taken together, our results suggest a critical role for the VAV interaction-dependent, extranuclear action of EZH2 in neoplastic transformation.
最近，我们报道了组蛋白甲基转移酶 EZH2 通过与细胞骨架重塑效应物 VAV 的相互作用以及对细胞骨架调节蛋白 Talin 的直接甲基化来控制白细胞迁移。然而，EZH2 的这种核外、非表观遗传功能是否对细胞转化和转移的启动有深远影响尚不清楚。在这里，我们表明 EZH2 增加了 Talin1 的甲基化和切割，从而增强了黏附周转率并促进了加速的肿瘤发生。通过靶向破坏 EZH2 与 VAV 的相互作用，这种转化能力被消除。此外，我们的研究表明，细胞质中的 EZH2 与癌症干细胞特性密切相关，并且过表达 EZH2、缺乏核定位信号的突变型 EZH2（EZH2ΔNLS）或模拟甲基化的 Talin1 突变体可显著促进 JAK2 依赖性 STAT3 激活和细胞转化。总之，我们的结果表明，EZH2 的 VAV 相互作用依赖性核外作用在肿瘤转化中起着关键作用。
