D-2-hydroxyglutarate is essential for maintaining oncogenic property of mutant IDH-containing cancer cells but dispensable for cell growth
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Shenghong Ma1, Bowen Jiang1, Wanglong Deng2, Zhong-Kai Gu1, Fei-Zhen Wu1, Tingting Li1, Yukun Xia1, Hui Yang1, Dan Ye1, Yue Xiong1,3, Kun-Liang Guan1,4
1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China
2State Key Laboratory of Medical Genomics and Shanghai Institute of Hematology, SJTU-SM, Shanghai 200025, China
3Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, North Carolina 27599, USA
4Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, USA
Dan Ye, e-mail: [email protected]
Yue Xiong, e-mail: [email protected]
Kun-Liang Guan, e-mail: [email protected]
Keywords: D-2-HG, IDH mutation, D2HGDH, tumorigenesis
Received: January 09, 2015 Accepted: February 09, 2015 Published: March 25, 2015
Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.
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