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The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway.

Original publication




Journal article


Nat commun

Publication Date





Astrocytes, Citric Acid Cycle, Glioma, Glutarates, HEK293 Cells, HeLa Cells, Humans, Intracellular Signaling Peptides and Proteins, Isocitrate Dehydrogenase, Jumonji Domain-Containing Histone Demethylases, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, PTEN Phosphohydrolase, TOR Serine-Threonine Kinases, Ubiquitination, beta-Transducin Repeat-Containing Proteins