Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms12700
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Funding
- Canada Foundation of Innovation
- Dr John R. and Clara M. Fraser Memorial Trust
- Terry Fox Foundation [116128]
- McGill University
- Fondation de l'Hopital Maisonneuve-Rosemont
- Cole Foundation
- Canadian Institutes of Health Research (CIHR) [MOP-133442, MOP-286437]
- Natural Sciences and Engineering Research Council of Canada (NSERC) [402880-2012]
- Arthritis Research UK [20522]
- NIHR Oxford Biomedical Research Unit
- Rosetrees Trust
- Abbvie [1097737]
- Bayer Healthcare
- Boehringer Ingelheim
- CIHR
- Canadian Foundation for Innovation
- Eli Lilly and Company
- Genome Canada
- GlaxoSmithKline
- Ontario Ministry of Economic Development and Innovation
- Janssen
- Novartis Research Foundation
- Pfizer
- Takeda
- Wellcome Trust
- Fonds de Recherche du Quebec - Sante (FRQS)/Fondation des Etoiles
- Canada Research Chair in Epigenetics of Aging and Cancer
- Rosetrees Trust [M289-F1, M289] Funding Source: researchfish
- Versus Arthritis [20522] Funding Source: researchfish
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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 alpha-ketoglutarate (alpha KG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from alpha KG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an alpha KG-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.
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