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Beyond Isocitrate Dehydrogenase Mutations: Emerging Mechanisms for the Accumulation of the Oncometabolite
Shufen Peng1,2, Huimin Chen1,2, Li Chen1,2
1Department of Nutrition and Food Hygiene, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Abstract:
2-Hydroxyglutarate (2-HG) is an unconventional oncometabolite of α-ketoglutarate. Isocitrate dehydrogenase mutation is generally acknowledged to be the main cause of 2-HG accumulation. In isocitrate dehydrogenase mutant tumors, 2-HG accumulation inhibits α-ketoglutarate/Fe(II)-dependent dioxygenases, resulting in epigenetic alterations. Recently, the increase of 2-HG has also been observed in the cases of mitochondrial dysfunction and hypoxia. In these cases, 2-HG not only inhibits α-ketoglutarate/Fe(II)-dependent dioxygenases to regulate epigenetics but also affects other cellular pathways, such as regulating hypoxia-inducible transcription factors and glycolysis. These provide a new perspective for the study of 2-HG.
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