The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway.
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.
Département de Biochimie et Médecine Moléculaire, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada H1T 2M4.
Mélissa
M
Carbonneau
Centre de Recherche sur le Cancer de l'Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec City, Quebec, Canada G1V 0A6.
Laurence
L
M Gagné
Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada H1T 2M4.
Marie-Eve
ME
Lalonde
Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada H1T 2M4.
Marie-Anne
MA
Germain
Département de Biochimie et Médecine Moléculaire, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada H1T 2M4.
Alena
A
Motorina
Brain Tumour Research Centre, Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.|Division of Neuropathology, Department of Pathology, McGill University, Montreal, Quebec, Canada H3A 2B4.
Marie-Christine
MC
Guiot
Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy, Québec City, Quebec, Canada G1V 4G5.|Département de Médecine, Faculté de Médecine, Université Laval, Québec City, Quebec, Canada G1V 0A6.
Blandine
B
Secco
Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada H3G 1Y6.|Department of Physiology, McGill University, Montréal, Quebec, Canada H3G 1Y6.
Emma E
EE
Vincent
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK.|Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7LD, UK.
Anthony
A
Tumber
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Ste-Catherine Road, Montréal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.
Laura
L
Hulea
Centre de Recherche sur le Cancer de l'Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec City, Quebec, Canada G1V 0A6.
Jonathan
J
Bergeman
Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington OX3 7DQ, UK.|Botnar Research Center, NIHR Oxford Biomedical Research Unit, Nuffield Department of Orthopaedics, Rheumatology &Musculoskeletal Sciences, Oxford OX3 7LD, UK.
Udo
U
Oppermann
Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada H3G 1Y6.|Department of Physiology, McGill University, Montréal, Quebec, Canada H3G 1Y6.
Russell G
RG
Jones
Institut universitaire de cardiologie et de pneumologie de Québec, 2725 chemin Sainte-Foy, Québec City, Quebec, Canada G1V 4G5.|Département de Médecine, Faculté de Médecine, Université Laval, Québec City, Quebec, Canada G1V 0A6.
Mathieu
M
Laplante
Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Côte-Ste-Catherine Road, Montréal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.
Ivan
0000-0002-5510-9762
I
Topisirovic
Brain Tumour Research Centre, Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, Canada H3A 2B4.
Kevin
K
Petrecca
Centre de Recherche sur le Cancer de l'Université Laval; Départements de Biologie moléculaire, biochimie médicale et pathologie, Université Laval, Québec City, Quebec, Canada G1V 0A6.|CHU de Québec-Axe Oncologie (Hôtel-Dieu de Québec), Québec City, Quebec Canada G1R 3S3.
Marc-Étienne
MÉ
Huot
Département de Biochimie et Médecine Moléculaire, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Quebec, Canada H3C 3J7.|Chromatin Structure and Cellular Senescence Research Unit, Maisonneuve-Rosemont Hospital Research Centre, Montréal, Quebec, Canada H1T 2M4.|Département de Médecine, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montréal, Quebec, Canada H3C 3J7.
Frédérick A
FA
Mallette
D001253:Astrocytes / Q000378:metabolism; D002952:Citric Acid Cycle; D005910:Glioma / Q000235:genetics; D005977:Glutarates / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
C471644:BTRC protein, human; D005977:Glutarates; D047908:Intracellular Signaling Peptides and Proteins; D044844:beta-Transducin Repeat-Containing Proteins; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human