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 iso...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2016
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| _version_ | 1797068431820849152 |
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| author | Carbonneau, M M Gagné, L Lalonde, M Germain, M Motorina, A Guiot, M Secco, B Vincent, E Tumber, A Hulea, L Bergeman, J Oppermann, U Jones, R Laplante, M Topisirovic, I Petrecca, K Huot, M Mallette, F |
| author_facet | Carbonneau, M M Gagné, L Lalonde, M Germain, M Motorina, A Guiot, M Secco, B Vincent, E Tumber, A Hulea, L Bergeman, J Oppermann, U Jones, R Laplante, M Topisirovic, I Petrecca, K Huot, M Mallette, F |
| author_sort | Carbonneau, M |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:10:40Z |
| format | Journal article |
| id | oxford-uuid:51aeee92-f67e-4d12-a0f8-c24b79c5d9d9 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:10:40Z |
| publishDate | 2016 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:51aeee92-f67e-4d12-a0f8-c24b79c5d9d92022-03-26T16:21:17ZThe oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathwayJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:51aeee92-f67e-4d12-a0f8-c24b79c5d9d9EnglishSymplectic Elements at OxfordSpringer Nature2016Carbonneau, MM Gagné, LLalonde, MGermain, MMotorina, AGuiot, MSecco, BVincent, ETumber, AHulea, LBergeman, JOppermann, UJones, RLaplante, MTopisirovic, IPetrecca, KHuot, MMallette, FThe 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. |
| spellingShingle | Carbonneau, M M Gagné, L Lalonde, M Germain, M Motorina, A Guiot, M Secco, B Vincent, E Tumber, A Hulea, L Bergeman, J Oppermann, U Jones, R Laplante, M Topisirovic, I Petrecca, K Huot, M Mallette, F The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title | The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title_full | The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title_fullStr | The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title_full_unstemmed | The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title_short | The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway |
| title_sort | oncometabolite 2 hydroxyglutarate activates the mtor signalling pathway |
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