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

Cell Rep. 2017 May 30;19(9):1846-1857. doi: 10.1016/j.celrep.2017.05.012.


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.

Keywords: 2-HG; IDH1 mutations; RIP3; hypermethylation; necroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferase 1 / metabolism*
  • DNA Methylation / drug effects*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Embryo, Mammalian / cytology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Glutarates / pharmacology*
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Mice
  • Mutation / genetics
  • Promoter Regions, Genetic*
  • Receptor-Interacting Protein Serine-Threonine Kinases / genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Transcription Initiation Site
  • Tumor Necrosis Factor-alpha / pharmacology


  • Glutarates
  • Tumor Necrosis Factor-alpha
  • alpha-hydroxyglutarate
  • Isocitrate Dehydrogenase
  • DNA (Cytosine-5-)-Methyltransferase 1
  • Dnmt1 protein, mouse
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse