期刊
CANCER CELL
卷 19, 期 1, 页码 17-30出版社
CELL PRESS
DOI: 10.1016/j.ccr.2010.12.014
关键词
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资金
- Chinese Ministry of Education [2009CB918401, 2009CB918600]
- Chinese National Science Foundation [30971485/C0706, 30600112, 30871255, 11079016]
- National Basic Research Program of China [2011CB965300, 2011CB910600]
- Shanghai key basic research projects, China [09JC1402300]
- NIH
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.
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