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

Abstract

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...

Intracellular cholesterol biosynthesis in enchondroma and chondrosarcoma

“…Previous studies have showed that expression of wild-type and mutant Idh1 is activated by SREBP1 and SREBP2 (encoded by Srebf1 and Srebf2) in livers as well as multiple cancer cell lines (23)(24)(25), and our study demonstrated that mutant Idh1 upregulated Srebf2. Since expression of mutant IDH1 has been previously shown to affect histone modification and DNA methylation (26,27), it may be possible that expression of Srebf2 in Idh1 mutant chondrocytes could be altered via epigenetic changes.…”

The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology

“…In particular, the utilization of glutamine carbon skeleton for energy production is based on this “semi-linearized” cycle, in which the glutamine skeleton enters the cycle as α-ketoglutarate, but escapes as malate at about half the cycle and reaches the cytosol where it is used in other pathways for NAPDH and pyruvate production, which are in turn involved in anabolic reactions and in anaerobic glycolysis (Figure 6 ). As an example, α-Ketoglutarate derived from glutamine skeleton can be a substrate of a cytosolic isoform of IDH (Ricoult et al, 2016 ). In this non-conventional reaction, isocitrate and citrate are produced for fatty acid synthesis (Mullen et al, 2014 ).…”

Abundance of d‐2‐hydroxyglutarate in G2/M is determined by FOXM1 in mutant IDH1‐expressing cells

“…SREBP1a and SREBP2 were also found to transcriptionally regulate IDH1 in sterol‐deficient conditions, therefore IDH1 is regulated by different transcription factors in cue to cellular pathways . However, in HT1080 synchronized cells, IDH1 protein levels are maintained at basal levels from G1/S boundary to G2/M (Fig.…”