Author/Authors :
Xu، نويسنده , , Wei and Yang، نويسنده , , Hui and Liu، نويسنده , , Ying and Yang، نويسنده , , Ying and Wang، نويسنده , , Ping and Kim، نويسنده , , Se-Hee and Ito، نويسنده , , Shinsuke and Yang، نويسنده , , Chen and Wang، نويسنده , , Pu and Xiao، نويسنده , , Meng-Tao and Liu، نويسنده , , Li-xia and Jiang، نويسنده , , Wen-qing and Liu، نويسنده , , Jing and Zhang، نويسنده , , Jin-ye and Wang، نويسنده , , Bin and Frye، نويسنده , , Stephen and Zhang، نويسنده , , Yi and Xu، نويسنده , , Yan-hui and Lei، نويسنده , , Qun-ying and Guan، نويسنده , , Kun-Liang and Zhao، نويسنده , , Shi-min and Xiong، نويسنده , , Yue، نويسنده ,
Abstract :
Summary
nd 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.
