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2-Oxoglutarate-Dependent Dioxygenases in Cancer

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2-Oxoglutarate-Dependent Dioxygenases in Cancer REVIEWS 2-Oxoglutarate-dependent dioxygenases in cancer Julie-Aurore Losman1,2, Peppi Koivunen3 and William G. Kaelin Jr. 1,4 ✉ Abstract | 2-Oxoglutarate-dependent dioxygenases (2OGDDs) are a superfamily of enzymes that play diverse roles in many biological processes, including regulation of hypoxia-inducible factor-mediated adaptation to hypoxia, extracellular matrix formation, epigenetic regulation of gene transcription and the reprogramming of cellular metabolism. 2OGDDs all require oxygen, reduced iron and 2-oxoglutarate (also known as α-ketoglutarate) to function, although their affinities for each of these co-substrates, and hence their sensitivity to depletion of specific co-substrates, varies widely. Numerous 2OGDDs are recurrently dysregulated in cancer. Moreover, cancer-specific metabolic changes, such as those that occur subsequent to mutations in the genes encoding succinate dehydrogenase, fumarate hydratase or isocitrate dehydrogenase, can dysregulate specific 2OGDDs. This latter observation suggests that the role of 2OGDDs in cancer extends beyond cancers that harbour mutations in the genes encoding members of the 2OGDD superfamily. Herein, we review the regulation of 2OGDDs in normal cells and how that regulation is corrupted in cancer. Enantiomer It has been known for many decades that cancer cells specific metabolites, including 2OG and its structur- One of two molecules that have display characteristic alterations in metabolism and ally related metabolites. For example, EGLN prolyl the same atomic formula and epigenetics. Many cancers divert glucose carbons 4-hydroxylases (also known as PHDs) and the FIH1 the same sequence of atomic towards glycolysis (canonical anaerobic metabolism) asparaginyl hydroxylase are 2OGDDs that act as cellular bonds but that differ in their 3D orientations insofar as they are and away from oxidative phosphorylation (canonical oxygen sensors by regulating the hypoxia-inducible tran- mirror images of each other. aerobic metabolism) even when oxygen is available scription factors HIF1α and HIF2α (collectively referred (known as the ‘Warburg effect’)1, and cancer genomes to hereafter as ‘HIFα’)13. HIF transcriptionally regulates Hypoxia often display global DNA hypomethylation as well hundreds of genes, including genes that contribute to A deficiency in the amount of as focal locus-specific increases in DNA and histone the Warburg effect and genes linked to DNA and histone oxygen being supplied to body 2,3 tissues. methylation . The question of whether such changes methylation. Other 2OGDDs play direct roles in the con- in metabolism and epigenetics actually cause cancer trol of DNA (TET and ABH enzymes) and histone (KDM 1 Department of Medical was controversial until oncogenic driver mutations enzymes) methylation, as well as mRNA processing Oncology, Dana-Farber Cancer Institute and Brigham were identified in metabolic and epigenetic genes. It is (FTO) and protein translation (OGFOD1, MINA53 14 and Women’s Hospital, now clear that some cancers are caused by mutations and NO66) . Boston, MA, USA. in the genes encoding fumarate hydratase (FH)4, suc- Some 2OGDDs are directly dysregulated in cancer, 2Division of Hematology, cinate dehydrogenase (SDH)5 and isocitrate dehydro- by amplification, silencing, deletion or mutation of Department of Medicine, genase (IDH)6,7, which lead to the accumulation of the their encoding genes (TABLE 1). Other 2OGDDs appear Brigham and Women’s 2-oxoglutarate (2OG; also known as α-ketoglutarate) to be indirectly dysregulated in cancer, by hypoxia Hospital, Boston, MA, USA. analogues fumarate, succinate and the R enantiomer and/or by the action of aberrantly accumulated metab- 3Faculty of Biochemistry (Fig. 1a) and Molecular Medicine, of 2-hydroxyglutarate (R-2HG), respectively . olites that possess pro-oncogenic activities (so-called Biocenter Oulu, Oulu Center Similarly, some cancers are caused by mutations in ‘oncometabolites’). Several 2OGDDs promote or sup- for Cell-Matrix Research, genes encoding epigenetic regulators such as the press tumour growth in preclinical cancer models, fur- University of Oulu, Oulu, EZH2 H3K27 methyltransferase8, the KMT2A H3K4 ther implicating the dysregulation of 2OGDD activity in Finland. methyltransferase9, the TET2 DNA hydroxylase10,11 and oncogenesis. However, much remains unknown about 4 Howard Hughes Medical the KDM6A H3K27 lysine demethylase12. the roles of specific 2OGDDs in cancer. The study of Institute (HHMI), Chevy Chase, MD, USA. 2-Oxoglutarate-dependent dioxygenases (2OGDDs) these enzymes has been further motivated by the obser- ✉e-mail: William_Kaelin@ are a superfamily of enzymes that sit at the nexus of vation that their activities can be modulated by small dfci.harvard.edu cancer metabolism and cancer epigenetics (BOx 1). molecules, suggesting that 2OGDDs could serve as ther- https://doi.org/10.1038/ These enzymes have the potential to sense oxygen, apeutic targets in cancer. Herein, we review our current s41568-020-00303-3 reactive oxygen species (ROS), iron availability and knowledge about the metabolic regulation of 2OGDD NATURE REVIEWS | CANCER REVIEWS activity and discuss how dysregulation of these activi- The 2OGDD reaction ties contributes to tumorigenesis. We also discuss some 2OGDDs all share the same reaction mechanism but of the outstanding questions in the field that warrant act on different substrates, including proteins, DNA, further investigation. RNA, fatty acids and other small molecules15 (BOx 1). a Pyruvate O HO PDH PC Oxaloacetate O CS Citrate O OH HO OH HO OH O O O O HO O MDH ACO Malate Isocitrate OH O HO OH HO OH O O O OH HO O FH IDH Fumarate Succinate 2OG Glutamate O O O NH2 HO HO HO OH HO OH OH OH OGDC GDH O SDH O O O O O SCS Mutant LDH IDH R-2HG S-2HG OH OH HO OH HO OH O O O O b DHA Ascorbate Fe2+ Fe3+ Substrate Substrate 2OGDD Substrate Substrate OH O O O HO Uncoupled 2OG decarboxylation HO OH + O OH + CO 2 2 2OG decarboxylation O O coupled with hydroxylation 2OG Succinate Fig. 1 | 2OG and its analogues and a schematic of the 2OGDD reaction. a | The tricarboxylic acid (TCA) cycle intermediate 2-oxoglutarate (2OG) and its structurally similar analogues. b | The substrate of the 2-oxoglutarate-dependent dioxygenase (2OGDD) reaction becomes hydroxylated in a reaction utilizing three co-substrates: divalent iron (Fe2+), which is coordinated to the catalytic site by two conserved histidine residues and a positively-charged arginine or lysine residue; 2OG; and molecular oxygen (O2), which provides the oxygen atom for the hydroxyl group. During catalysis, 2OG becomes decarboxylated to succinate and CO2. The hydroxylated substrate can undergo further non-enzymatic modification, such as demethylation. Structural 2OG analogues, including fumarate, succinate, R-2-hydroxyglutarate (R-2HG) and S-2-hydroxyglutarate (S-2HG), have the potential to act as competitive inhibitors of 2OGDDs. Ascorbate is not a direct co-substrate of the 2OGDD reaction but supports the reaction by preventing inadvertent iron oxidation from occurring during an uncoupled reaction. ACO, aconitase; CS, citrate synthase; FH, fumarate hydratase; IDH, isocitrate dehydrogenase; LDH, lactate dehydrogenase; MDH, malate dehydrogenase; OGDC, oxoglutarate dehydrogenase complex; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; SCS, succinyl-CoA synthase; SDH, succinate dehydrogenase. www.nature.com/nrc REVIEWS Box 1 | List of 2OGDDs and other proteins that utilize and regulate 2OG 2-Oxoglutarate-dependent dioxygenases • Protein hydroxylases: ASPH, EGLN1–3, FIH1, JMJD4–7, LEPRE1, LEPREL1, LEPREL2, MINA53, NO66, OGFOD1, P4HA1–3, P4HTM and PLOD1–3 • Histone demethylases: KDM2A, KDM2B, KDM3A, KDM3B, KDM4A, KDM4B, KDM4C, KDM4D, KDM5A, KDM5B, KDM5C, KDM5D, KDM6A, KDM6B, KDM6C, KDM7A, KDM7B and KDM9 • Nucleic acid oxygenases: ABH1, ABH2, ABH3, ABH5, ABH8, FTO, TET1–3 and TYW5 • Fatty acid and small-molecule oxygenases: BBOX1, PHYH and TMLHE • Unassigned catalytic function: ABH4, ABH6, ABH7, ASPHD1, ASPHD2, HSPBAP1, JARID2, JMJD8, KDM3C, OGFOD2, OGFOD3, PHF2 and PHYHD1 Other proteins involved in 2OG metabolism • Transaminases (see figure, part a): AADAT, ABAT, AGXT, AGXT2, BCAT1, BCAT2, CCBL1, CCBL2, GFPT1, GFPT2, GOT1, GOT2, GPT, GPT2, OAT, PSAT1 and TAT • Dehydrogenases (see figure, part b): AASS, ADHFE1, ALDH1B1, ALDH2, ALDH3A2, ALDH7A1, ALDH9A1, DHTKD1, DLD, GDH1, GDH2, IDH1, IDH2, IDH3A, IDH3B, IDH3G, OGDH, OGDHL, PHGDH, (d/R)-2HGDH and (l/S)-2HGDH • Transporters: SLC22A6, SLC22A7, SLC22A8, SLC22A11, SLC22A20, SLC22A25, SLC22A13 and SLC22A12 • Other: DLST and NIT2 a L-Leucine 2-Oxoglutarate 4-Methyl-2-oxopentanoate L-Glutamate O O O NH2 + HO OH + HO OH OH OH NH2 O O BCAT O O O b L-Glutamate 2-Oxoglutarate NAD+ NADH + H+ NH2 O HO OH HO OH O O + O O H2O NH4 GDH 2OG, 2-oxoglutarate; 2OGDD, 2-oxoglutarate-dependent dioxygenase. 2OGDDs all require the same co-substrates — dioxygen its enantiomer S-2HG, can act as competitive inhibitors 20–23 (O2), which provides the oxygen atom for hydroxylation, of 2OGDDs , modulating 2OGDD activity in both divalent iron (Fe2+) and 2OG — and yield a hydroxylated physiologic and pathophysiologic states (FIGS 1a and 2; (Fig. 1b) TABle 2 product, CO2 and succinate . Catalysis follows an ). Although other mechanisms of regulation ordered sequence. First, active site-bound Fe2+ coordi- of 2OGDDs have been reported, including alternative nates 2OG binding in a bidentate manner. Next, substrate splicing and translation initiation24–26, post-translational binding to the active site displaces an Fe2+-ligated
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