Premium
The oncometabolite 2‐hydroxyglutarate inhibits histone lysine demethylases
Author(s) -
Chowdhury Rasheduzzaman,
Yeoh Kar Kheng,
Tian YaMin,
Hillringhaus Lars,
Bagg Eleanor A,
Rose Nathan R,
Leung Ivanhoe K H,
Li Xuan S,
Woon Esther C Y,
Yang Ming,
McDonough Michael A,
King Oliver N,
Clifton Ian J,
Klose Robert J,
Claridge Timothy D W,
Ratcliffe Peter J,
Schofield Christopher J,
Kawamura Akane
Publication year - 2011
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2011.43
Subject(s) - demethylase , isocitrate dehydrogenase , histone , oxygenase , histone h3 , biology , biochemistry , hypoxia inducible factors , methylation , histone methylation , epigenetics , lysine , methyltransferase , enzyme , gene , dna methylation , gene expression , amino acid
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 ε ‐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.