2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter
2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter
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2-HG 通过刺激 RIP3 启动子的 DNMT1 依赖性高甲基化来抑制坏死性凋亡
DOI：
10.1016/j.celrep.2017.05.012
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发表时间：
2017-05-30
期刊：
影响因子：
8.8
通讯作者：
Han, Jiahuai
中科院分区：
文献类型：
--
作者：
Yang, Zhentao;Jiang, Bin;Han, Jiahuai
2-羟基戊二酸-（2-HG）介导的TET 2活性抑制影响异柠檬酸脱氢酶1和2（IDH 1/2）突变细胞中的DNA超甲基化。在这里，我们表明，2-HG也调节DNA甲基转移酶1（DNMT 1）介导的DNA甲基化。RIP 3启动子的DNMT 1依赖性超甲基化发生在IDH 1 R132 Q敲入突变小鼠胚胎成纤维细胞（MEFs）和2-HG处理的野生型（WT）MEFs中。我们发现，2-HG结合到DNMT 1，并刺激其与RIP 3启动子的关联，诱导甲基化，减少RIP 3蛋白，从而削弱RIP 3依赖性坏死性凋亡。在人神经胶质瘤样品中，RIP 3蛋白水平与IDH 1 R132 H水平负相关。此外，异位表达的RIP 3在转化IDH 1突变的MEFs抑制肿瘤的生长来源于这些细胞移植到裸鼠。因此，我们的研究揭示了2-HG诱导的DNA超甲基化的机制，并表明受损的坏死性凋亡有助于IDH 1/2突变驱动的肿瘤发生。
2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R132Q knockin mutant mouse embryonic fibroblast (MEFs) and 2-HG-treated wild-type (WT) MEFs. We found that 2-HG bound to DNMT1 and stimulated its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. In human glioma samples, RIP3 protein levels correlated negatively with IDH1 R132H levels. Furthermore, ectopic expression of RIP3 in transformed IDH1-mutated MEFs inhibited the growth of tumors derived from these cells following transplantation into nude mice. Thus, our research sheds light on a mechanism of 2-HG-induced DNA hypermethylation and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1/2 mutations.