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Drosophila Larvae Synthesize the Putative Oncometabolite L-2-Hydroxyglutarate During Normal Developmental Growth

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Drosophila Larvae Synthesize the Putative Oncometabolite L-2-Hydroxyglutarate During Normal Developmental Growth Drosophila larvae synthesize the putative oncometabolite L-2-hydroxyglutarate during normal developmental growth Hongde Lia, Geetanjali Chawlaa, Alexander J. Hurlburta, Maria C. Sterretta, Olga Zaslaverb, James Coxc, Jonathan A. Kartyd, Adam P. Rosebrockb,e, Amy A. Caudyb,e, and Jason M. Tennessena,1 aDepartment of Biology, Indiana University, Bloomington, IN 47405; bDepartment of Molecular Genetics, University of Toronto, Toronto, ON, Canada M5S 3E1; cDepartment of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112; dDepartment of Chemistry, Indiana University, Bloomington, IN 47405; and eDonnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada M5S 3E1 Edited by Jasper Rine, University of California, Berkeley, CA, and approved December 23, 2016 (received for review August 23, 2016) L-2-hydroxyglutarate (L-2HG) has emerged as a putative oncome- neomorphic mutations in the active site of isocitrate dehydrogenase tabolite that is capable of inhibiting enzymes involved in metab- 1 or 2 (IDH1/2) (5). Tumors that harbor these IDH1/2 mutations olism, chromatin modification, and cell differentiation. However, inappropriately convert 2-oxoglutarate (2OG) to D-2HG, which acts despite the ability of L-2HG to interfere with a broad range of as a competitive inhibitor of 2-oxoglutarate–dependent dioxygenases cellular processes, this molecule is often characterized as a [2OGDs; e.g., Jmj histone lysine demethylases, ten-eleven trans- metabolic waste product. Here, we demonstrate that Drosophila location (TET) enzyme family] (3, 6–9). As a result, IDH1/2 mutant larvae use the metabolic conditions established by aerobic glycol- cells experience widespread chromatin remodeling and changes in ysis to both synthesize and accumulate high concentrations of gene expression and are unable to differentiate properly (8, 9). L-2HG during normal developmental growth. A majority of the Although most oncometabolite research is focused on D-2HG, larval L-2HG pool is derived from glucose and dependent on the the L-2-hydroxyglutarate (L-2HG) enantiomer is an even more Drosophila estrogen-related receptor (dERR), which promotes potent 2OGD inhibitor, and high L-2HG levels are associated L-2HG synthesis by up-regulating expression of the Drosophila with renal cell carcinomas, gliomas, and a neurometabolic dis- homolog of lactate dehydrogenase (dLdh). We also show that order known as L-2-hydroxyglutaric aciduria (10–12). Unlike dLDH is both necessary and sufficient for directly synthesizing D-2HG, however, L-2HG has no known role in metabolism and L-2HG and the Drosophila homolog of L-2-hydroxyglutarate dehy- eukaryotes lack an enzyme dedicated to L-2HG synthesis. In- drogenase (dL2HGDH), which encodes the enzyme that breaks stead, L-2HG is considered an aberrant metabolite produced by down L-2HG, is required for stage-specific degradation of the the nonspecific activity of enzymes such as malate dehydrogenase, L-2HG pool. In addition, dLDH also indirectly promotes L-2HG accu- lactate dehydrogenase A (LDHA), and lactate dehydrogenase C mulation via synthesis of lactate, which activates a metabolic feed- (12–18). Consistent with these observations, L-2HG accumula- GENETICS forward mechanism that inhibits dL2HGDH activity and stabilizes tion in cancer cells does not result from ectopic synthesis; rather, L-2HG levels. Finally, we use a genetic approach to demonstrate it stems from decreased expression of the enzyme L-2-hydrox- that dLDH and L-2HG influence position effect variegation and yglutarate dehydrogenase (L2HGDH), which is solely responsible DNA methylation, suggesting that this compound serves to coor- dinate glycolytic flux with epigenetic modifications. Overall, our for L-2HG degradation (10, 19). Therefore, most studies suggest studies demonstrate that growing animal tissues synthesize L-2HG that neither healthy tissues nor cancer cells appear capable of in a controlled manner, reveal a mechanism that coordinates glu- regulating L-2HG production. This model of L-2HG synthesis, cose catabolism with L-2HG synthesis, and establish the fly as a however, has been challenged by a recent study of T lymphocytes, unique model system for studying the endogenous functions of L-2HG during cell growth and proliferation. Significance 2-hydroxyglutarate | LDH | lactate | Warburg effect | Oncometabolites are small molecules that promote tumor for- estrogen-related receptor mation and growth. L-2-hydroxyglutarate (L-2HG) is a putative oncometabolite that is associated with gliomas and renal cell ne of the hallmarks of cancer is a dramatic reprograming of carcinomas, as well as a severe neurometabolic disorder known Ocellular metabolism that results in enhanced biosynthesis as L-2-hydroxyglutaric aciduria. However, despite that L-2HG is (1). These metabolic changes are particularly apparent in tumors commonly considered a metabolic waste product, this com- that use the Warburg effect, also referred to as aerobic glycolysis, pound was recently discovered to control immune cell fate, a metabolic program characterized by elevated levels of glucose thereby demonstrating that it has endogenous functions in consumption and enhanced lactate production (1, 2). By activating healthy animal cells. Here, we find that the fruit fly, Drosophila aerobic glycolysis, tumors are able to synthesize macromolecules melanogaster, also synthesizes high concentrations of L-2HG rapidly from glycolytic intermediates. In addition, elevated levels during normal larval growth. Our discovery establishes the fly of lactate dehydrogenase (LDH) activity allow proliferating cells as a genetic model for studying this putative oncometabolite in + to synthesize lactate and maintain the NAD levels required for healthy animal tissues. high rates of glucose catabolism and biomass production (1). Author contributions: H.L., G.C., A.A.C., and J.M.T. designed research; H.L., G.C., A.J.H., The metabolic reprogramming of cancer cells, however, extends M.C.S., J.C., J.A.K., and J.M.T. performed research; H.L., G.C., O.Z., A.P.R., A.A.C., and J.M.T. beyond biosynthesis, as many tumors also generate progrowth contributed new reagents/analytic tools; H.L., G.C., A.J.H., M.C.S., J.C., and J.M.T. analyzed metabolites, or oncometabolites, that promote tumor formation data; and H.L. and J.M.T. wrote the paper. via nonmetabolic means. Most notable among these compounds The authors declare no conflict of interest. is D-2-hydroxyglutarate (D-2HG), which is associated with cancers This article is a PNAS Direct Submission. such as gliomas and acute myelogenous leukemias (3). Although 1To whom correspondence should be addressed. Email: [email protected]. γ D-2HG is generated as a normal byproduct of -hydroxybutyrate This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. metabolism (4), oncogenic D-2HG production is the result of 1073/pnas.1614102114/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1614102114 PNAS | February 7, 2017 | vol. 114 | no. 6 | 1353–1358 Downloaded by guest on September 25, 2021 which revealed that these immune cells generate L-2HG as a A Drosophila development B L2 larvae means of controlling cell fate and gene expression (20). Fur- Emb Larva wpp Adult thermore, both hypoxia and the disruption of mitochondrial 2 metabolism cause human cells to generate high levels of L-2HG, 100 indicating that synthesis of this compound might alleviate oxi- dative stress (17, 21–23). These observations hint at diverse en- 1 dogenous roles for L-2HG and suggest that the function of this 50 putative oncometabolite should be further studied in healthy 2HG (nmol/mg) tissues. To address this need, we have established the fruit fly Relative [2HG] 0 0 Drosophila melanogaster as a genetic model system for studying 1820317654 9 L- D- L-2HG in the context of aerobic glycolysis and rapid tissue growth. Staged Timepoint (see legend) The fly is ideally suited to study the molecular mechanisms that link glycolytic flux to biosynthesis. Similar to cancer cells, growing C Kc167 BG1-c1 D L2 larvae Drosophila larvae up-regulate glycolysis, the pentose phosphate 1 1 U-13C-glucose pathway, and lactate production as means of supporting the nearly 0.8 0.8 U-13C-proline 200-fold increase in body mass that occurs during this develop- mental stage (24). The resulting metabolic program exhibits the 0.6 0.6 hallmark characteristics of aerobic glycolysis and establishes the 0.4 0.4 fly as a powerful in vivo model for studying this metabolic state. 0.2 Furthermore, studies in the fly were the first to demonstrate that 0.2 2HG (nmol/mg) 0 the estrogen-related receptor (ERR) family of nuclear receptors Fraction of labelled 2HG 0 acts as a conserved transcriptional regulator of aerobic glycolysis L- D- L- D- 0 5 15 25 (24–26). Here, we extend the metabolic parallels between Dro- Time (hours) sophila development and tumor growth by demonstrating that Fig. 1. Drosophila larvae accumulate high concentrations of L-2HG. (A) Relative the Drosophila estrogen-related receptor (dERR) also promotes abundance of 2HG in a w1118 background. Staged time points are as follows: L-2HG synthesis. Moreover, we determine that the larval L-2HG (1) embryos (Emb; 0–12 h after egg laying), (2) Emb (12–24 h after egg laying), pool is largely derived from glucose oxidation and synthesized (3) L1 larvae, (4) L2 larvae, (5) early-L3 larvae (0–12 h after L2-L3 molt), (6) mid-L3 by the Drosophila ortholog of LDH (dLDH), thereby establishing larvae (24–36 h after L2-L3 molt), (7) wandering L3 larvae, (8) white prepupae a direct link between larval glycolytic metabolism and L-2HG (wpp), (9) adult females (3 d posteclosion), and (10) adult males (3 d posteclosion). production. Finally, we demonstrate that dLDH and L-2HG are Data are represented as box plots (n = 6). The concentrations of D-2HG and L-2HG key regulators of position effect variegation (PEV) and DNA in midsecond-instar w1118 larvae (B)andtheDrosophila cell lines Kc167 and BG1-c1 (C) are shown.
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