The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.

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.

• Authors: Rasheduzzaman Chowdhury, Kar Kheng Yeoh, Ya-Min Tian, Lars Hillringhaus, Eleanor A Bagg, Nathan R Rose, Ivanhoe K H Leung, Xuan S Li, Esther C Y Woon, Ming Yang, Michael A McDonough, Oliver N King, Ian J Clifton, Robert J Klose, Timothy D W Claridge, Peter J Ratcliffe, Christopher J Schofield, Akane Kawamura
• Journal: EMBO reports (EMBO Rep) Vol. 12 Issue 5 Pg. 463-9 (May 2011) ISSN: 1469-3178 [Electronic] England
• PMID: 21460794 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glutarates
• Repressor Proteins
• alpha-hydroxyglutarate
• Mixed Function Oxygenases
• Isocitrate Dehydrogenase
• HIF1AN protein, human
• Histone Demethylases
• Jumonji Domain-Containing Histone Demethylases
• Procollagen-Proline Dioxygenase
• KDM4A protein, human

Topics

• Cell Line, Tumor
• Crystallography
• Glutarates (metabolism)
• Histone Demethylases (antagonists & inhibitors)
• Humans
• Inhibitory Concentration 50
• Isocitrate Dehydrogenase (genetics, metabolism)
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, chemistry)
• Magnetic Resonance Spectroscopy
• Mass Spectrometry
• Mixed Function Oxygenases
• Models, Molecular
• Mutation (genetics)
• Neoplasms (enzymology, genetics)
• Procollagen-Proline Dioxygenase (antagonists & inhibitors)
• Repressor Proteins (antagonists & inhibitors, chemistry)
• Signal Transduction (physiology)