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Publication - Dr Emma Vincent

    The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

    Citation

    Carbonneau, M, Gagné, LM, Lalonde, M-E, Germain, M-A, Motorina, A, Guiot, M-C, Secco, B, Vincent, EE, Tumber, A, Hulea, L, Bergeman, J, Oppermann, U, Jones, RG, Laplante, M, Topisirovic, I, Petrecca, K, Huot, M-&#x &am;p; Mallette, FA, 2016, ‘The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway’. Nature Communications, vol 7., pp. 12700

    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.

    Full details in the University publications repository