Cited by 78Epigenetics and DNA MethylationGlioma Diagnosis and TreatmentCancer, Hypoxia, and Metabolism

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

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Yang, Zhentao, Jiang, Bin, Wang, Yan, Ni, Hengxiao, Zhang, Jia, Xia, Jinmei, Shi, Minggang, Hung, Li-Man +4 more·2017·Cell Reports

Abstract

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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Crossref · 10.1016/j.celrep.2017.05.012

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  • The emerging role of Krebs cycle intermediates opens the possibility of manipulating levels and impacts of mitochondrial metabolites within the matrix, the rest of the cell, or after release into circulation.

    “the emerging role of Krebs cycle intermediates in many central biomedical pathways opens up the possibility of extending mitochondrial pharmacology164-167 to manipulating the levels and impacts of mitochondrial metabolites both within the matrix, the rest of the cell, or following their release from the cell into the circulation.”

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Authors
Yang, Z., Jiang, B., Wang, Y., Ni, H., Zhang, J., Xia, J., Shi, M., Hung, L.-M., Ruan, J., Mak, T. W., Li, Q., & Han, J.
Affiliations
  • Xiamen University (CN)
  • Tianjin Huanhu Hospital (CN)
  • Chang Gung University (TW)
  • University Health Network (CA)
Corresponding author
  • Li, Qinxi
  • Han, Jiahuai
Venue
Cell Reports
Publisher
Elsevier BV
Published
2017-05
Volume
19
Issue
9
Pages
1846-1857
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2619358118
Cited by
78
References
61
Citations by year
2026: 7 · 2025: 7 · 2024: 9 · 2023: 11 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 2 · 2014: 1
FWCI
2.35
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81402285, 31571473, 91029304, 31330047, 31420103910, 81630042, 81372702)
  • Higher Education Discipline Innovation Project (B12001)
  • Fundamental Research Funds for the Central Universities (10120100002, 20720140552)
  • Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
  • National Key Research and Development Program of China (2014CB541804, 2013CB944903, 2015CB553800)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords
2-hydroxyglutarate, necroptosis, RIPK3, DNMT1, DNA hypermethylation, IDH1 mutation, IDH2 mutation, promoter methylation, glioma, carcinogenesis, epigenetic regulation, isocitrate dehydrogenase
MeSH terms
DNA (Cytosine-5-)-Methyltransferase 1, Animals, Embryo, Mammalian, Fibroblasts, Glutarates, Humans, Isocitrate Dehydrogenase, Mutation, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha, Down-Regulation, Apoptosis, DNA Methylation, Transcription Initiation Site, Cell Line, Tumor, Mice, Receptor-Interacting Protein Serine-Threonine Kinases, Carcinogenesis

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