2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Zhentao Yang, Bin Jiang, Yan Wang, Hengxiao Ni, Jia Zhang, Jinmei Xia, Minggang Shi, Li-Man Hung, Jingsong Ruan, Tak Wah Mak, Qinxi Li, Jiahuai Han
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.

Graphical abstract

Teaser

Yang et al. report that oncometabolite 2-HG produced by tumor-associated IDH1 mutation physically binds to DNMT1 and stimulates its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. Loss of RIP3-mediated necroptosis contributes to tumorigenesis driven by 2-HG.


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