Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent Dioxygenases

被引：2298

作者：

Xu, Wei ^{[1
,2
]}

Yang, Hui ^{[1
,2
]}

Liu, Ying ^{[3
]}

Yang, Ying ^{[1
]}

Wang, Ping ^{[1
]}

Kim, Se-Hee ^{[9
]}

Ito, Shinsuke ^{[9
,11
]}

Yang, Chen ^{[6
]}

Wang, Pu ^{[1
,2
]}

Xiao, Meng-Tao ^{[1
,2
]}

Liu, Li-xia ^{[5
]}

Jiang, Wen-qing ^{[1
,2
]}

Liu, Jing ^{[6
]}

Zhang, Jin-ye ^{[2
]}

Wang, Bin ^{[4
]}

Frye, Stephen ^{[10
]}

Zhang, Yi ^{[9
,11
,12
]}

Xu, Yan-hui ^{[1
]}

Lei, Qun-ying ^{[2
,5
]}

Guan, Kun-Liang ^{[1
,2
,5
,7
,8
]}

Zhao, Shi-min ^{[1
,2
]}

Xiong, Yue ^{[1
,2
,9
,12
]}

机构：

[1] Fudan Univ, Shanghai Med Sch, Sch Life Sci, State Key Lab Genet Engn, Shanghai 20032, Peoples R China

[2] Fudan Univ, Shanghai Med Sch, Mol & Cell Biol Lab, Inst Biomed Sci, Shanghai 20032, Peoples R China

[3] Fudan Univ, Shanghai Med Sch, Dept Pathol, Shanghai 20032, Peoples R China

[4] Fudan Univ, Shanghai Med Sch, Dept Biol Chem, Shanghai 20032, Peoples R China

[5] Fudan Univ, Shanghai Med Sch, Dept Biochem, Shanghai 20032, Peoples R China

[6] Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Plant Physiol & Ecol, Key Lab Synthet Biol, Shanghai 200032, Peoples R China

[7] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA

[8] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[9] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[10] Univ N Carolina, Ctr Integrat Chem Biol & Drug Discovery, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA

[11] Univ N Carolina, Howard Hughes Med Inst, Chapel Hill, NC 27599 USA

[12] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA

来源：

CANCER CELL | 2011年 / 19卷 / 01期

基金：

美国国家科学基金会;

关键词：

ACUTE MYELOID-LEUKEMIA; INTEGRATED GENOMIC ANALYSIS; HIF-ALPHA; 2-OXOGLUTARATE OXYGENASES; TRANSCRIPTIONAL ACTIVITY; HISTONE DEMETHYLATION; PROLYL HYDROXYLATION; IDH2; MUTATIONS; BREAST-CANCER; FAMILY;

D O I：

10.1016/j.ccr.2010.12.014

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

1DH1 and 1DH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha-ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5-methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-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 1DH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations.

引用

页码：17 / 30

页数：14

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