The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway.
The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway.
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DOI：
10.1038/ncomms12700
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发表时间：
2016-09-14
影响因子：
16.6
通讯作者：
Mallette, Frederick A.
中科院分区：
文献类型：
--
作者：
Carbonneau, Melissa;Gagne, Laurence M.;Lalonde, Marie-Eve;Germain, Marie-Anne;Motorina, Alena;Guiot, Marie-Christine;Secco, Blandine;Vincent, Emma E.;Tumber, Anthony;Hulea, Laura;Bergeman, Jonathan;Oppermann, Udo;Jones, Russell G.;Laplante, Mathieu;Topisirovic, Ivan;Petrecca, Kevin;Huot, Marc-Etienne;Mallette, Frederick A.
三羧酸（TCA）循环酶异柠檬酸脱氢酶1和2 （IDH1/2）中癌症相关突变的鉴定突出了异常代谢功能可促进致癌的流行观点。IDH1/2通常催化异柠檬酸氧化脱羧生成α-酮戊二酸酯（αKG）。在胶质瘤和急性髓性白血病中，IDH1/2突变赋予功能获得，导致αKG产生肿瘤代谢物r -2-羟基戊二酸（2HG）。本研究表明，突变的IDH1/2产生2HG通过抑制KDM4A（一种赖氨酸去甲基化酶家族的α kg依赖性酶）导致mTOR的激活。此外，KDM4A与DEP结构域含有mtor相互作用蛋白（detor）相关，detor是mTORC1/2的负调节因子。KDM4A的缺失降低了DEPTOR蛋白的稳定性。我们的研究结果通过揭示TCA循环缺陷与典型PI3K/AKT/TSC1-2通路下游mTOR功能正向调节之间的前所未有的联系，为突变体IDH1/2的致癌活性提供了额外的分子机制。异柠檬酸脱氢酶1和2的致癌突变导致肿瘤代谢物r -2-羟基戊二酸的产生。在这里，作者表明，肿瘤代谢物通过抑制KDM4A活性调节DEPTOR的稳定性，以不依赖PTEN/ pi3k的方式促进mTOR的激活。
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. Oncogenic mutations of isocitrate dehydrogenases 1 and 2 result in the production of the oncometabolite R-2-hydroxyglutarate. Here the authors show that the oncometabolite promotes mTOR activation in a PTEN/PI3K-independent manner by regulating DEPTOR stability via inhibition of KDM4A activity.
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影响因子：
16
作者：
Gao D;Inuzuka H;Tan MK;Fukushima H;Locasale JW;Liu P;Wan L;Zhai B;Chin YR;Shaik S;Lyssiotis CA;Gygi SP;Toker A;Cantley LC;Asara JM;Harper JW;Wei W
通讯作者：
Wei W
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
16
作者：
Kim, DH;Sarbassov, DD;Sabatini, DM
通讯作者：
Sabatini, DM
影响因子：
--
作者：
Hutchinson, Sue E.;Leveridge, Melanie V.;Argyrou, Argyrides
通讯作者：
Argyrou, Argyrides