Ricoult Stéphane J H, Dibble Christian C, Asara John M, Manning Brendan D
Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
Mol Cell Biol. 2016 Aug 26;36(18):2384-95. doi: 10.1128/MCB.00163-16. Print 2016 Sep 15.
Sterol regulatory element binding protein (SREBP) is a major transcriptional regulator of the enzymes underlying de novo lipid synthesis. However, little is known about the SREBP-mediated control of processes that indirectly support lipogenesis, for instance, by supplying reducing power in the form of NAPDH or directing carbon flux into lipid precursors. Here, we characterize isocitrate dehydrogenase 1 (IDH1) as a transcriptional target of SREBP across a spectrum of cancer cell lines and human cancers. IDH1 promotes the synthesis of lipids specifically from glutamine-derived carbons. Neomorphic mutations in IDH1 occur frequently in certain cancers, leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG). We found that SREBP induces the expression of oncogenic IDH1 and influences 2-HG production from glucose. Treatment of cells with 25-hydroxycholesterol or statins, which respectively inhibit or activate SREBP, further supports SREBP-mediated regulation of IDH1 and, in cells with oncogenic IDH1, carbon flux into 2-HG.
固醇调节元件结合蛋白（SREBP）是从头合成脂质相关酶的主要转录调节因子。然而，对于SREBP介导的间接支持脂肪生成过程的调控知之甚少，例如，通过以烟酰胺腺嘌呤二核苷酸磷酸（NAPDH）的形式提供还原力或引导碳通量进入脂质前体。在此，我们将异柠檬酸脱氢酶1（IDH1）鉴定为跨一系列癌细胞系和人类癌症中SREBP的转录靶点。IDH1特别促进从谷氨酰胺衍生的碳合成脂质。IDH1中的新形态突变在某些癌症中频繁出现，导致致癌代谢物2-羟基戊二酸（2-HG）的产生。我们发现SREBP诱导致癌性IDH1的表达，并影响葡萄糖生成2-HG。用25-羟基胆固醇或他汀类药物处理细胞，分别抑制或激活SREBP，进一步支持SREBP介导的IDH1调节，以及在具有致癌性IDH1的细胞中，碳通量进入2-HG。
