The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

Mélissa Carbonneau, Laurence M. Gagné, Marie-Eve Lalonde, Marie-Anne Germain, Alena Motorina, Marie-Christine Guiot, Blandine Secco, Emma E. Vincent, Anthony Tumber, Laura Hulea, Jonathan Bergeman, Udo Oppermann, Russell G. Jones, Mathieu Laplante, Ivan Topisirovic, Kevin Petrecca, Marc-Étienne Huot () and Frédérick A. Mallette ()
Additional contact information
Mélissa Carbonneau: Université de Montréal
Laurence M. Gagné: Centre de Recherche sur le Cancer de l’Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval
Marie-Eve Lalonde: Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre
Marie-Anne Germain: Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre
Alena Motorina: Université de Montréal
Marie-Christine Guiot: Brain Tumour Research Centre, Montreal Neurological Institute and Hospital, McGill University
Blandine Secco: Institut universitaire de cardiologie et de pneumologie de Québec
Emma E. Vincent: Goodman Cancer Research Centre, McGill University
Anthony Tumber: Structural Genomics Consortium, University of Oxford
Laura Hulea: Lady Davis Institute for Medical Research, Jewish General Hospital
Jonathan Bergeman: Centre de Recherche sur le Cancer de l’Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval
Udo Oppermann: Structural Genomics Consortium, University of Oxford
Russell G. Jones: Goodman Cancer Research Centre, McGill University
Mathieu Laplante: Institut universitaire de cardiologie et de pneumologie de Québec
Ivan Topisirovic: Lady Davis Institute for Medical Research, Jewish General Hospital
Kevin Petrecca: Brain Tumour Research Centre, Montreal Neurological Institute and Hospital, McGill University
Marc-Étienne Huot: Centre de Recherche sur le Cancer de l’Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval
Frédérick A. Mallette: Université de Montréal

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12700

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