1. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases
- Author
-
Ming Yang, Eleanor A.L. Bagg, Ya-Min Tian, Kar Kheng Yeoh, Rasheduzzaman Chowdhury, Lars Hillringhaus, Oliver N. King, Akane Kawamura, Xuan S Li, Ivanhoe K. H. Leung, Christopher J. Schofield, Esther C. Y. Woon, Peter J. Ratcliffe, Robert J. Klose, Ian J. Clifton, Michael A. McDonough, Nathan R. Rose, and Timothy D. W. Claridge
- Subjects
Models, Molecular ,Jumonji Domain-Containing Histone Demethylases ,Magnetic Resonance Spectroscopy ,Procollagen-Proline Dioxygenase ,Biology ,Biochemistry ,Mass Spectrometry ,Mixed Function Oxygenases ,Glutarates ,Inhibitory Concentration 50 ,Cell Line, Tumor ,Neoplasms ,Histone methylation ,Genetics ,Humans ,Molecular Biology ,Histone Demethylases ,Crystallography ,Scientific Reports ,Molecular biology ,Isocitrate Dehydrogenase ,Repressor Proteins ,Isocitrate dehydrogenase ,Histone ,Hypoxia-inducible factors ,Mutation ,biology.protein ,Demethylase ,Procollagen-proline dioxygenase ,Signal Transduction - Abstract
Mutations in isocitrate dehydrogenases (IDHs) have a gain-of-function effect leading to R(-)-2-hydroxyglutarate (R-2HG) accumulation. By using biochemical, structural and cellular assays, we show that either or both R- and S-2HG inhibit 2-oxoglutarate (2OG)-dependent oxygenases with varying potencies. Half-maximal inhibitory concentration (IC(50)) values for the R-form of 2HG varied from approximately 25 μM for the histone N(ɛ)-lysine demethylase JMJD2A to more than 5 mM for the hypoxia-inducible factor (HIF) prolyl hydroxylase. The results indicate that candidate oncogenic pathways in IDH-associated malignancy should include those that are regulated by other 2OG oxygenases than HIF hydroxylases, in particular those involving the regulation of histone methylation.
- Published
- 2011