The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases.
EMBO Rep
; 12(5): 463-9, 2011 May.
Article
em En
| MEDLINE
| ID: mdl-21460794
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(É)-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.
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Modelos Moleculares
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Histona Desmetilases
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Glutaratos
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Isocitrato Desidrogenase
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Neoplasias
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article