IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells

Shechter, Ishaiahu; Dai, Peihua; Huo, Liang; Guan, Guimin

doi:10.1194/jlr.m300285-jlr200

Cited by 88 publications

(90 citation statements)

References 69 publications

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“…This would be especially attractive if increased flux through wild-type IDH1 can be shown to be dependent on the activation of growth factor signaling pathways. Prior evidence has linked IDH1 expression levels to the activity of the sterol regulatory element-binding protein transcription factor (39). Increasing IDH1 expression has been suggested to alter cellular and organismal physiology by increasing the production of cytosolic NADPH (40).…”

Section: Discussionmentioning

confidence: 99%

The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

Ward

Lü

Cross

et al. 2013

Journal of Biological Chemistry

151

141

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Background: Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations can lead to 2-hydroxyglutarate (2HG) accumulation in cancer. Results: 2HG production from IDH mutants varies with subcellular localization and dependence on substrate production from the persistent wild-type IDH allele. Conclusion: IDH1 but not IDH2 mutants require a wild-type IDH partner for 2HG production. Significance: Differential 2HG production may explain the prognosis of IDH1/2 mutant cancers.

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Section: Discussionmentioning

confidence: 99%

The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

Ward

Lü

Cross

et al. 2013

Journal of Biological Chemistry

151

141

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“…Isocitrate dehydrogenase 1 (IDH1) is another enzyme that can support lipogenesis either through NADPH production or, through reductive carboxylation, facilitating the flux of carbon to lipids (15)(16)(17). The IDH1 promoter has an identifiable consensus SRE, and a previous study using in vitro electrophoretic mobility shift and reporter assays found that SREBP could bind directly to this sequence (18). However, the extent to which SREBP regulates IDH1 gene expression and the downstream consequences were not determined.…”

mentioning

confidence: 99%

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

Ricoult

Dibble

Asara

et al. 2016

Molecular and Cellular Biology

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bSterol 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. The sterol regulatory element (SRE) binding protein (SREBP) family of transcription factors is activated by sterol depletion, growth factor signaling pathways, and oncogenes to induce the expression of genes encoding the major enzymes of de novo lipid synthesis (1-5). In sterol-replete conditions, inactive SREBP is held in the endoplasmic reticulum (ER). Upon sterol depletion, SREBP traffics from the ER to the Golgi apparatus, where it is proteolytically processed, leading to the release of a mature, active SREBP transcription factor (6, 7). The mature SREBP then translocates to the nucleus and binds SRE-containing gene promoters to induce transcription. The three SREBP isoforms are produced from two different genes: SREBF1, which encodes SREBP1a and SREBP1c, and SREBF2, which encodes SREBP2. Although studies of isoform-specific functions of the SREBPs in the liver have pointed to a role for SREBP1c in fatty acid and triglyceride synthesis and SREBP2 in cholesterol synthesis (8), SREBP targets appear to be more redundantly regulated in other settings (see, for example, references 3 and 4).The transcriptional activation of de novo lipid synthesis genes by SREBP is well studied, but less is known about the regulation of auxiliary genes that indirectly support lipogenesis by providing NADPH or directing carbon flux into lipids (8). Overexpression of mature, active SREBP in the liver of mice increases the transcription of genes encoding glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and malic enzyme 1, which are all major sources of NADPH production (9, 10). Similarly, mature SREBP increases the expression of acetyl coenzyme A (acetyl-CoA) synthetase (ACSS2) and ATP-citrate lyase (ACLY), as well as the mitochondrial citrate transporter (SLC25A1), which facilitate the flux of carbons into lipids from acetate and citrate, respectively (11-14). Isocitrate dehydrogenase 1 (IDH1) is another enzyme that can support lipogenesis either through NADPH production or, throug...

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“…As a-KG and NADPH are important components for lipogenesis (38,39) and as the mutated IDH enzyme consumes both compounds and lacks reductive carboxylation capacity, we hypothesized that phospholipid metabolism is altered in IDH1-mutated glioma. To test this hypothesis, we applied in vivo 31 P MR spectroscopic imaging (MRSI) to four unique and representative human glioma models growing orthotopically in mice (40), one carrying the IDH1-R132H mutation (41).…”

Section: Introductionmentioning

confidence: 99%

IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

et al. 2014

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Many patients with glioma harbor specific mutations in the isocitrate dehydrogenase gene IDH1 that associate with a relatively better prognosis. IDH1-mutated tumors produce the oncometabolite 2-hydroxyglutarate. Because IDH1 also regulates several pathways leading to lipid synthesis, we hypothesized that IDH1-mutant tumors have an altered phospholipid metabolite profile that would impinge on tumor pathobiology. To investigate this hypothesis, we performed 31 P-MRS imaging in mouse xenograft models of four human gliomas, one of which harbored the IDH1-R132H mutation.31 P-MR spectra from the IDH1-mutant tumor displayed a pattern distinct from that of the three IDH1 wild-type tumors, characterized by decreased levels of phosphoethanolamine and increased levels of glycerophosphocholine. This spectral profile was confirmed by ex vivo analysis of tumor extracts, and it was also observed in human surgical biopsies of IDH1-mutated tumors by 31 P highresolution magic angle spinning spectroscopy. The specificity of this profile for the IDH1-R132H mutation was established by in vitro 31 P-NMR of extracts of cells overexpressing IDH1 or IDH1-R132H. Overall, our results provide evidence that the IDH1-R132H mutation alters phospholipid metabolism in gliomas involving phosphoethanolamine and glycerophosphocholine. These new noninvasive biomarkers can assist in the identification of the mutation and in research toward novel treatments that target aberrant metabolism in IDH1-mutant glioma. Cancer Res; 74(17); 4898-907. Ó2014 AACR.

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IDH1 gene transcription is sterol regulated and activated by SREBP-1a and SREBP-2 in human hepatoma HepG2 cells

Cited by 88 publications

References 69 publications

The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

Sterol Regulatory Element Binding Protein Regulates the Expression and Metabolic Functions of Wild-Type and Oncogenic IDH1

IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

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