IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives.
Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in multiple types of human cancer. Mutations targeting IDH1 and IDH2 result in simultaneous loss of their normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new function, the production of 2-hydroxyglutarate (2-HG). 2-HG is structurally similar to α-KG, and acts as an α-KG antagonist to competitively inhibit multiple α-KG-dependent dioxygenases, including both lysine histone demethylases and the ten-eleven translocation family of DNA hydroxylases. Abnormal histone and DNA methylation are emerging as a common feature of tumors with IDH1 and IDH2 mutations and may cause altered stem cell differentiation and eventual tumorigenesis. Therapeutically, unique features of IDH1 and IDH2 mutations make them good biomarkers and potential drug targets.
Molecular and Cell Biology Lab, Institutes of Biomedical Sciences and School of Life Sciences, Fudan University, Shanghai, P R China.
Hui
H
Yang
Dan
D
Ye
Kun-Liang
KL
Guan
Yue
Y
Xiong
D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D019175:DNA Methylation; D005977:Glutarates / Q000378:metabolism; D056466:Histone Demethylases / Q000037:antagonists & inhibitors; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D005977:Glutarates; D007656:Ketoglutaric Acids; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D056466:Histone Demethylases