Nagasaki University School of Medicine, Nagasaki 852-8523, Japan.
Radiation Biology Center, Kyoto University, Kyoto 606-8501, Japan.
Mol Cell. 2016 Oct 6;64(1):176-188. doi: 10.1016/j.molcel.2016.09.012.
How deregulation of chromatin modifiers causes malignancies is of general interest. Here, we show that histone H2A T120 is phosphorylated in human cancer cell lines and demonstrate that this phosphorylation is catalyzed by hVRK1. Cyclin D1 was one of ten genes downregulated upon VRK1 knockdown in two different cell lines and showed loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In vitro, H2A T120 phosphorylation and H2A K119 ubiquitylation are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, expression of a phosphomimetic H2A T120D increased H3 K4 methylation. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. These results suggest that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene expression, including upregulated cyclin D1, which promotes oncogenic transformation.
染色质修饰物的去调控如何导致恶性肿瘤是普遍关注的问题。在这里，我们表明组蛋白 H2A T120 在人类癌细胞系中发生磷酸化，并证明这种磷酸化是由 hVRK1 催化的。在两种不同的细胞系中，VRK1 敲低后，有 10 个基因下调，其中包括 cyclin D1，并且其启动子区域失去 H2A T120 磷酸化和增加 H2A K119 泛素化，导致细胞生长受损。在体外，H2A T120 磷酸化和 H2A K119 泛素化是相互抑制的，这表明组蛋白磷酸化间接激活染色质。此外，表达磷酸化模拟 H2A T120D 增加了 H3 K4 甲基化。最后，VRK1 和 H2A T120D 突变组蛋白都转化了 NIH/3T3 细胞。这些结果表明，hVRK1 对组蛋白 H2A T120 的磷酸化导致了异常的基因表达，包括上调的 cyclin D1，从而促进了致癌转化。
