Authors:
Wei Xu, 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
Summary:
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.
Source:
Cancer Cell; Vol. 19, Issue 1, 17-30 (01/18/11)