MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis

Terunuma, Atsushi; Putluri, Nagireddy; Mishra, Prachi; Mathé, Ewy A.; Dorsey, Tiffany H.; Yi, Ming; Wallace, Tiffany A.; Issaq, Haleem J.; Zhou, Ming; Killian, J. Keith; Stevenson, Holly; Karoly, Edward D.; Chan, Kwong; Samanta, Susmita; Prieto, DaRue A.; Hsu, Tiffany; Kurley, Sarah J.; Putluri, Vasanta; Sonavane, Rajni; Edelman, Daniel C.; Wulff, Jacob; Starks, Adrienne M.; Yang, Yinmeng; Kittles, Rick A.; Yfantis, Harry G.; Lee, Dong Hoon; Ioffe, Olga B.; Schiff, Rachel; Stephens, Robert M.; Meltzer, Paul S.; Veenstra, Timothy D.; Westbrook, Thomas F.; Sreekumar, Arun; Ambs, Stefan

doi:10.1172/jci71180

Cited by 345 publications

(413 citation statements)

References 76 publications

(91 reference statements)

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“…4e). The locus encoding PHGDH is frequently amplified in breast cancer and melanoma 34,35 , and elevated 2HG levels have been detected in primary breast tumors with aggressive features but no IDH mutation 36 . Thus, determining the chirality of 2HG should help elucidate which metabolic pathway contributes to 2HG production in various cancer settings.…”

Section: Resultsmentioning

confidence: 99%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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The metabolite 2-hydroxyglutarate (2HG) can be produced as either a D(R)- or L(S)- enantiomer, each of which inhibits alpha-ketoglutarate (αKG)-dependent enzymes involved in diverse biologic processes. Oncogenic mutations in isocitrate dehydrogenase produce D-2HG, which causes a pathologic blockade in cell differentiation. On the other hand, oxygen limitation leads to accumulation of L-2HG, which can facilitate physiologic adaptation to hypoxic stress in both normal and malignant cells. Here we demonstrate that purified lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) catalyze stereospecific production of L-2HG via ‘promiscuous’ reduction of the alternative substrate αKG. Acidic pH enhances production of L-2HG by promoting a protonated form of αKG that binds to a key residue in the substrate-binding pocket of LDHA. Acid-enhanced production of L-2HG leads to stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in normoxia. These findings offer insights into mechanisms whereby microenvironmental factors influence production of metabolites that alter cell fate and function.

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Section: Resultsmentioning

confidence: 99%

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

et al. 2017

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“…In addition to phosphoglycerate dehydrogenase, two other enzymes are known to catalyze the reduction of ␣-ketoglutarate to D-2HG in mammals: isocitrate dehydrogenase and the 4-hydroxybutyrate-␣-ketoglutarate transhydrogenase ADHFE1 (13). While point mutations in the isocitrate dehydrogenases IDH1 and IDH2 are well known to lead to a loss of the normal catalytic activity and a gain of D-2HG forming activity both in D-2-hydroxyglutaric acidurias and in a number of cancers (9,66), there is also evidence that wild-type IDH1 and IDH2 contribute to D-2HG formation in mammalian cells (11,15). The yeast orthologs of the human NADP-dependent IDH1 and IDH2 enzymes are Idp1 (mitochondrial), Idp2 (cytosolic), and Idp3 (peroxisomal).…”

Section: Identification Of a New Type Of Enzymatic Activity For Degramentioning

confidence: 99%

“…Interestingly, somatic IDH1 (cytosolic isocitrate dehydrogenase) and IDH2 mutations leading to increased D-2HG production have also been identified in a number of cancers, including gliomas and acute myelogenous leukemia (10). Increased 2HG levels have in addition been detected in human breast tumors with wild-type isocitrate dehydrogenase (IDH) (11). D-2HG is therefore suspected to act as an oncometabolite (10).…”

mentioning

confidence: 99%

Saccharomyces cerevisiae Forms d-2-Hydroxyglutarate and Couples Its Degradation to d-Lactate Formation via a Cytosolic Transhydrogenase

Becker-Kettern

Paczia

Conrotte

et al. 2016

Journal of Biological Chemistry

109

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The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3⌬ knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2⌬ knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to ␣-ketoglutarate. Depletion of D-lactate levels in the dld3⌬, but not in the dld2⌬ mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to ␣-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3-phosphoglycerate in the main serine biosynthesis pathway, in addition reduce ␣-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1. 2-Hydroxyglutarate (2HG)3 is a 5-carbon dicarboxylic acid that was first detected in human urine in the late 1970s (1).Because of the hydroxyl group on the second carbon, 2HG exists under two enantiomeric configurations (L or D) that can be separated by gas or liquid chromatography after derivatization with another chiral compound and that can therefore be differentially assayed in biological samples using GC-MS or LC-MS methods (2, 3). The interest in 2HG increased when it was found to accumulate in urine of patients with suspected inborn errors of metabolism (4, 5). Most 2-hydroxyglutaric aciduria patients present elevations of either L-2HG or D-2HG in their extracellular fluids, and the clinical phenotype depends on the configuration of the accumulated organic acid. More recently, cases of "combined D,L-hydroxyglutaric aciduria" have been reported (6).2-Hydroxyglutaric acidurias remained enigmatic diseases because neither L-2HG nor D-2HG are intermediates of any known metabolic pathway, and the causal gene deficiencies were only discovered many years after the first patient case reports. It is now established that L-2-hydroxyglutaric aciduria is caused by loss-of-function mutations in the L2HGDH gene, encoding a specific L-2HG dehydrogenase, whereas in many cases D-2-hydroxyglutaric aciduria results from loss-of-function mutations in the D2H...

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“…MYC was found to upregulate glutamine transporters and induce the expression of GLS at the mRNA and protein level 48,145 , and to drive a glutamine-fueled TCA cycle and glutathione production in hypoxia 151 . Glutamine in MYC-driven cells can be used for de novo proline synthesis 82 or production of the oncometabolite 2-hydroxyglutarate in breast cancer 152 , although the latter finding has not been independently corroborated. Infection by adenovirus or Kaposi's sarcoma-associated herpesvirus (KSHV) both increase MYC expression and glutamine metabolism 153,154 , and in the case of KSHV this may be a part of early tumorigenesis that eventually leads to Kaposi's sarcoma.…”

Section: Oncogenes and Glutamine Metabolismmentioning

confidence: 99%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

221

108

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis

Cited by 345 publications

References 76 publications

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

Saccharomyces cerevisiae Forms d-2-Hydroxyglutarate and Couples Its Degradation to d-Lactate Formation via a Cytosolic Transhydrogenase

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

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