Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases

  • Cancer Cell. 2011 Jan 18;19(1):17-30. doi: 10.1016/j.ccr.2010.12.014.
Wei Xu  1 ,  Hui Yang ,  Ying Liu ,  Ying Yang ,  Ping Wang ,  Se-Hee Kim ,  Shinsuke Ito ,  Chen Yang ,  Pu Wang ,  Meng-Tao Xiao ,  Li-xia Liu ,  Wen-qing Jiang ,  Jing Liu ,  Jin-ye Zhang ,  Bin Wang ,  Stephen Frye ,  Yi Zhang ,  Yan-hui Xu ,  Qun-ying Lei ,  Kun-Liang Guan ,  Shi-min Zhao ,  Yue Xiong
Affiliations
  • 1. State Key Laboratory of Genetic Engineering, School of Life Sciences, Shanghai Medical School, Fudan University, Shanghai 20032, China.
PMID: 21251613 DOI: 10.1016/j.ccr.2010.12.014
Abstract

IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple α-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as α-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce α-KG and accumulate an α-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

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