Journal
CELL REPORTS
Volume 19, Issue 9, Pages 1846-1857Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.012
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Funding
- National Basic Research Program of China (973 Program) [2015CB553800, 2013CB944903, 2014CB541804]
- National Natural Science Foundation of China [91029304, 31420103910, 31330047, 81630042, 81372702, 81402285, 31571473]
- 111 Project [B12001]
- Fundamental Research Funds for the Central Universities [20720140552, 10120100002]
- National Science Foundation of China [J1310027]
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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.
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