Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Dang, Lenny; White, David W.; Größ, Stefan; Bennett, Bryson D.; Bittinger, Mark; Driggers, Edward M.; Fantin, Valeria R.; Jang, Hyun Gyung; Jin, Shengfang; Keenan, Marie C.; Marks, Kevin M.; Prins, Robert M.; Ward, Patrick S.; Yen, Katharine; Liau, Linda M.; Rabinowitz, Joshua D.; Cantley, Lewis C.; Thompson, Craig B.; Heiden, Matthew G Vander; Su, Shinsan M.

doi:10.1038/nature09132

Cited by 592 publications

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“…Oncogenic hot spot mutations in IDH1 disrupt its normal homeostatic role, since the mutant enzyme is unable to catalyze the reductive carboxylation reaction and the alternative reaction producing 2-HG consumes NADPH (23,51). In line with previous work showing that transcriptional regulation of oncogenic IDH1 R132C can disrupt 2-HG production (47), we show that SREBP activation and inhibition reciprocally increase and decrease IDH1-dependent 2-HG production in IDH1 R132C cells.…”

Section: Discussionsupporting

confidence: 75%

“…The oncogenic mutations primarily affect the same catalytic arginine residue in IDH1 (R132) and IDH2 (R172) and are neomorphic in nature. Oncogenic IDH1 and IDH2 lose the ability to produce isocitrate and convert ␣-KG to 2-hydroxyglutarate (2-HG), the levels of which are greatly elevated in the tumors and plasma of patients harboring these mutations (23,24). 2-HG is an oncometabolite closely resembling ␣-KG and therefore inhibits ␣-KG-dependent enzymes, which promote tumor development through epigenetic changes influencing cellular differentiation (25)(26)(27).…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 75%

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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“…Whereas IDH3 catalyzes the third step of the TCA cycle while converting NAD+ to NADH in the mitochondria, IDH1 and IDH2 catalyze the same reaction outside the context of the TCA cycle, and utilize NADP+ instead of NAD+. Mutations in IDH1/2, mostly encoding amino acid switches at R132/R100 in IDH1 and R140/R172 in IDH2, generates a gain-offunction phenotype in which isocitrate is aberrantly converted to 2-hydroxyglutarate (2-HG), which accumulates in cells and tissues [96][97][98][99] (Figure 1). 2-HG acts as an oncometabolite, and due to its structural similarity with α-KG, interferes with enzymes requiring α-KG for their function, including the TET enzymes and enzymes involved in histone modifications, such as the Jumonjis [64,100].…”

Section: Disruption Of 5-hmc Levels In Hematological Malignanciesmentioning

confidence: 99%

5-hydroxymethylcytosine in cancer: significance in diagnosis and therapy

Vasanthakumar

Godley

2015

Cancer Genetics

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“…8 Review of the peaks of interest is then conducted by the analyst using other software (e.g., that supplied by the instrument vendor). While this process has proven effective for discovering metabolites that respond strongly to biological perturbations, 14–16 the need to separately review raw data and manually re-enter any peaks misannotated by automated processing methods is tedious when the goal is metabolome-wide quantitation. 17–19 Accordingly, it would be useful to have software that couples automated feature detection and peak alignment with online data visualization and annotation.…”

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confidence: 99%

Metabolomic Analysis and Visualization Engine for LC−MS Data

Melamud¹,

Vastag²,

Rabinowitz³

2010

Anal. Chem.

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563

466

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Metabolomic analysis by liquid chromatography–high-resolution mass spectrometry results in data sets with thousands of features arising from metabolites, fragments, isotopes, and adducts. Here we describe a software package, Metabolomic Analysis and Visualization ENgine (MAVEN), designed for efficient interactive analysis of LC–MS data, including in the presence of isotope labeling. The software contains tools for all aspects of the data analysis process, from feature extraction to pathway-based graphical data display. To facilitate data validation, a machine learning algorithm automatically assesses peak quality. Users interact with raw data primarily in the form of extracted ion chromatograms, which are displayed with overlaid circles indicating peak quality, and bar graphs of peak intensities for both unlabeled and isotope-labeled metabolite forms. Click-based navigation leads to additional information, such as raw data for specific isotopic forms or for metabolites changing significantly between conditions. Fast data processing algorithms result in nearly delay-free browsing. Drop-down menus provide tools for the overlay of data onto pathway maps. These tools enable animating series of pathway graphs, e.g., to show propagation of labeled forms through a metabolic network. MAVEN is released under an open source license at http://maven.princeton.edu.

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Cancer-associated IDH1 mutations produce 2-hydroxyglutarate

Cited by 592 publications

References 1 publication

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

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

5-hydroxymethylcytosine in cancer: significance in diagnosis and therapy

Metabolomic Analysis and Visualization Engine for LC−MS Data

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