2-HG Inhibits Necroptosis By Stimulating DNMT1-Dependent Hypermethylation Of The RIP3 Promoter

The mutation in isocitrate dehydrogenases 1(IDH1)at R132 confers a new function to this enzyme,which can produce a new metabolite named 2-hydroxyglutarate(2-HG).It has been proved that 2-HG can inhibit the activity of a-KG-dependent ten eleven translocation dioxygenases(TET2)due to the similar structure between 2-HG and a-KG.And this kind of inhibition will lead to DNA hypermethylation in cells expressing mutant IDH1.Here we found that DNA methyltransferase 1(DNMT1)is a new target of 2-HG.2-HG produced by mutant IDH1 resulted in hypermethylation of the RIP3 promoter,which can consequently reduce protein level of RIP3 and thus suppress the necroptosis.And we discovered that the hypermethylation of the RIP3 promoter is mediated by DNMT1.2-HG can enhance the interaction between DNMT1 and RIP3 promoter,and then reduce the expression level of RIP3.In addition,the inhibition of RIP3 protein level had a good correlation with IDH1 mutant status in human glioma samples.And ectopic expression of RIP3 in transformed IDH1-mutated MEF inhibited the growth of tumors.In conclusion,our research sheds light on a previously unknown mechanism of 2-HG-induced DNA hypermethylation,and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1 mutations.