title: Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1.
abstract: 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.
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Stéphane J H
authors.initials: SJ
authors.lastname: Ricoult
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Dibble
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA bmanning@hsph.harvard.edu.
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*
chemical_list: D005977:Glutarates; D008055:Lipids; D051779:Sterol Regulatory Element Binding Proteins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D005947:Glucose