IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives

Clinical Cancer Research - Tập 18 Số 20 - Trang 5562-5571 - 2012
Hui Yang1,2, Dan Ye1,2, Kun‐Liang Guan1, Yue Xiong1
1Authors' Affiliations: 1Molecular and Cell Biology Lab, Institutes of Biomedical Sciences and School of Life Sciences, Fudan University, Shanghai, P R China; 2Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California; and 3Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina
2Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina

Tóm tắt

Abstract

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. Clin Cancer Res; 18(20); 5562–71. ©2012 AACR.

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