Oncometabolite 2-hydroxyglutarate is a Competitive Inhibitor of α-ketoglutarate-dependent Dioxygenases

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2011 Jan 22

PMID 21251613

Citations 1488

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

Affiliations

Soon will be listed here.

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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