D2HGDH regulates alpha-ketoglutarate levels and dioxygenase function by modulating IDH2.

Abstract

Isocitrate dehydrogenases (IDH) convert isocitrate to alpha-ketoglutarate (α-KG). In cancer, mutant IDH1/2 reduces α-KG to D2-hydroxyglutarate (D2-HG) disrupting α-KG-dependent dioxygenases. However, the physiological relevance of controlling the interconversion of D2-HG into α-KG, mediated by D2-hydroxyglutarate dehydrogenase (D2HGDH), remains obscure. Here we show that wild-type D2HGDH elevates α-KG levels, influencing histone and DNA methylation, and HIF1α hydroxylation. Conversely, the D2HGDH mutants that we find in diffuse large B-cell lymphoma are enzymatically inert. D2-HG is a low-abundance metabolite, but we show that it can meaningfully elevate α-KG levels by positively modulating mitochondrial IDH activity and inducing IDH2 expression. Accordingly, genetic depletion of IDH2 abrogates D2HGDH effects, whereas ectopic IDH2 rescues D2HGDH-deficient cells. Our data link D2HGDH to cancer and describe an additional role for the enzyme: the regulation of IDH2 activity and α-KG-mediated epigenetic remodelling. These data further expose the intricacies of mitochondrial metabolism and inform on the pathogenesis of D2HGDH-deficient diseases.

• Authors: An-Ping Lin, Saman Abbas, Sang-Woo Kim, Manoela Ortega, Hakim Bouamar, Yissela Escobedo, Prakash Varadarajan, Yuejuan Qin, Jessica Sudderth, Eduard Schulz, Alexander Deutsch, Sumitra Mohan, Peter Ulz, Peter Neumeister, Dinesh Rakheja, Xiaoli Gao, Andrew Hinck, Susan T Weintraub, Ralph J DeBerardinis, Heinz Sill, Patricia L M Dahia, Ricardo C T Aguiar
• Journal: Nature communications (Nat Commun) Vol. 6 Pg. 7768 (Jul 16 2015) ISSN: 2041-1723 [Electronic] England
• PMID: 26178471 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• HIF1A protein, human
• Histones
• Hypoxia-Inducible Factor 1, alpha Subunit
• Ketoglutaric Acids
• Alcohol Oxidoreductases
• IDH2 protein, human
• Isocitrate Dehydrogenase
• D2HGDH protein, human
• Dioxygenases

Topics

• Alcohol Oxidoreductases (genetics)
• Blotting, Western
• Cell Line, Tumor
• DNA Methylation (genetics)
• Dioxygenases (metabolism)
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Histones (metabolism)
• Humans
• Hydroxylation (genetics)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Isocitrate Dehydrogenase (genetics, metabolism)
• Ketoglutaric Acids (metabolism)
• Lymphoma, Large B-Cell, Diffuse (genetics)
• Methylation
• Real-Time Polymerase Chain Reaction