The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway

被引：144

作者：

Carbonneau, Melissa ^{[1
,2
]}

Gagne, Laurence M. ^{[3
,4
,5
,6
]}

Lalonde, Marie-Eve ^{[2
]}

Germain, Marie-Anne ^{[2
]}

Motorina, Alena ^{[1
,2
]}

Guiot, Marie-Christine ^{[7
,8
]}

Secco, Blandine ^{[9
,10
]}

Vincent, Emma E. ^{[11
,12
]}

Tumber, Anthony ^{[13
,14
]}

Hulea, Laura ^{[15
,16
]}

Bergeman, Jonathan ^{[3
,4
,5
,6
]}

Oppermann, Udo ^{[13
,17
]}

Jones, Russell G. ^{[11
,12
]}

Laplante, Mathieu ^{[9
,10
]}

Topisirovic, Ivan ^{[15
,16
]}

Petrecca, Kevin ^{[7
]}

Huot, Marc-Etienne ^{[3
,4
,5
,6
,18
]}

Mallette, Frederick A. ^{[1
,2
,19
]}

机构：

[1] Univ Montreal, Dept Biochim & Med Mol, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada

[2] Maisonneuve Rosemont Hosp, Chromatin Struct & Cellular Senescence Res Unit, Res Ctr, Montreal, PQ H1T 2M4, Canada

[3] Univ Laval, Ctr Rech Canc, Quebec City, PQ G1V 0A6, Canada

[4] Univ Laval, Dept Mol Biol, Quebec City, PQ G1V 0A6, Canada

[5] Univ Laval, Dept Biochim Med, Quebec City, PQ G1V 0A6, Canada

[6] Univ Laval, Dept Pathol, Quebec City, PQ G1V 0A6, Canada

[7] McGill Univ, Brain Tumour Res Ctr, Montreal Neurol Inst & Hosp, Dept Neurol & Neurosurg, 3801 Univ St, Montreal, PQ H3A 2B4, Canada

[8] McGill Univ, Div Neuropathol, Dept Pathol, Montreal, PQ H3A 2B4, Canada

[9] Inst Univ Cardiol & Pneumol Quebec, 2725 Chemin St Foy, Quebec City, PQ G1V 4G5, Canada

[10] Univ Laval, Dept Med, Fac Med, Quebec City, PQ G1V 0A6, Canada

[11] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada

[12] McGill Univ, Dept Physiol, Montreal, PQ H3G 1Y6, Canada

[13] Univ Oxford, Struct Genom Consortium, Old Rd Campus,Roosevelt Dr, Headington OX3 7DQ, England

[14] Univ Oxford, Target Discovery Inst, NDM Res Bldg,Roosevelt Dr, Oxford OX3 7LD, England

[15] Jewish Gen Hosp, Lady Davis Inst Med Res, 3755 Cote Ste Catherine Rd, Montreal, PQ H3T 1E2, Canada

[16] McGill Univ, Dept Oncol, 546 Pine Ave West, Montreal, PQ H2W 1S6, Canada

[17] Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Botnar Res Ctr, NIHR Oxford Biomed Res Unit, Oxford OX3 7LD, England

[18] CHU Quebec Axe Oncol, Hotel Dieu Quebec, Quebec City, PQ G1R 3S3, Canada

[19] Univ Montreal, Dept Med, CP 6128,Succursale Ctr Ville, Montreal, PQ H3C 3J7, Canada

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

英国惠康基金; 加拿大自然科学与工程研究理事会; 加拿大健康研究院;

关键词：

BETA-TRCP; HISTONE DEMETHYLATION; GLUTAMINE-METABOLISM; BINDING PARTNER; IDH2; MUTATIONS; JMJD2; FAMILY; INHIBITOR; DEGRADATION; RAPTOR; REPRESSION;

D O I：

10.1038/ncomms12700

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

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