2-Oxoglutarate-dependent dioxygenases in cancer

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: 2OG and its analogues and a schematic of the 2OGDD reaction.
Fig. 2: Kinetic and inhibitory values of 2OGDD for co-substrates and 2OG analogues.
Fig. 3: Structural basis for the differential oxygen-sensing capacities of KDM6A and KDM6B JmjC domains.
Fig. 4: Dysregulation of 2OGDD activity by hypoxia.

References

  1. 1.

    DeBerardinis, R. J. & Chandel, N. S. We need to talk about the Warburg effect. Nat. Metab. 2, 127–129 (2020).

    PubMed  Google Scholar 

  2. 2.

    Baylin, S. B. & Jones, P. A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a019505 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Feinberg, A. P., Koldobskiy, M. A. & Gondor, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Schmidt, C., Sciacovelli, M. & Frezza, C. Fumarate hydratase in cancer: a multifaceted tumour suppressor. Semin. Cell Dev. Biol. 98, 15–25 (2020).

    CAS  PubMed  Google Scholar 

  5. 5.

    Gill, A. J. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology 72, 106–116 (2018).

    PubMed  Google Scholar 

  6. 6.

    Dang, L., Yen, K. & Attar, E. C. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27, 599–608 (2016).

    CAS  PubMed  Google Scholar 

  7. 7.

    Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bowman, R. L. & Levine, R. L. TET2 in normal and malignant hematopoiesis. Cold Spring Harb. Perspect. Med. https://doi.org/10.1101/cshperspect.a026518 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Gaidzik, V. I. et al. TET2 mutations in acute myeloid leukemia (AML): results from a comprehensive genetic and clinical analysis of the AML study group. J. Clin. Oncol. 30, 1350–1357 (2012).

    CAS  PubMed  Google Scholar 

  12. 12.

    Wang, L. & Shilatifard, A. UTX mutations in human cancer. Cancer Cell 35, 168–176 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Kaelin, W. G. Jr. & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    CAS  PubMed  Google Scholar 

  14. 14.

    Herr, C. Q. & Hausinger, R. P. Amazing diversity in biochemical roles of FeII/2-oxoglutarate oxygenases. Trends Biochem. Sci. 43, 517–532 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Islam, M. S., Leissing, T. M., Chowdhury, R., Hopkinson, R. J. & Schofield, C. J. 2-Oxoglutarate-dependent oxygenases. Annu. Rev. Biochem. 87, 585–620 (2018).

    CAS  PubMed  Google Scholar 

  16. 16.

    Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5, 343–354 (2004).

    CAS  PubMed  Google Scholar 

  17. 17.

    Koivunen, P., Hirsila, M., Kivirikko, K. I. & Myllyharju, J. The length of peptide substrates has a marked effect on hydroxylation by the hypoxia-inducible factor prolyl 4-hydroxylases. J. Biol. Chem. 281, 28712–28720 (2006). This study shows that peptide substrate length affects the O2 Km values of EGLN-mediated hydroxylation reactions, thereby demonstrating that these reactions are strongly influenced by in vitro reaction conditions.

    CAS  PubMed  Google Scholar 

  18. 18.

    Flashman, E., Davies, S. L., Yeoh, K. K. & Schofield, C. J. Investigating the dependence of the hypoxia-inducible factor hydroxylases (factor inhibiting HIF and prolyl hydroxylase domain 2) on ascorbate and other reducing agents. Biochem. J. 427, 135–142 (2010). This study shows that hydroxylation of HIF proteins by EGLN prolyl hydroxylases and FIH is stimulated by reducing agents in an enzyme and substrate-specific manner.

    CAS  PubMed  Google Scholar 

  19. 19.

    Briggs, K. J. et al. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine. Cell 166, 126–139 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Tarhonskaya, H. et al. Studies on the interaction of the histone demethylase KDM5B with tricarboxylic acid cycle intermediates. J. Mol. Biol. 429, 2895–2906 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Laukka, T. et al. Fumarate and succinate regulate expression of hypoxia-inducible genes via TET enzymes. J. Biol. Chem. 291, 4256–4265 (2016). This study shows that fumarate and succinate competitively inhibit the TET family of 5-mc hydroxylases, providing a biochemical basis for their function as oncometabolites.

    CAS  PubMed  Google Scholar 

  22. 22.

    Laukka, T., Myllykoski, M., Looper, R. E. & Koivunen, P. Cancer-associated 2-oxoglutarate analogues modify histone methylation by inhibiting histone lysine demethylases. J. Mol. Biol. 430, 3081–3092 (2018). This study shows that fumarate and succinate competitively inhibit the KDM family of histone lysine demethylases, providing a biochemical basis for their function as oncometabolites.

    CAS  PubMed  Google Scholar 

  23. 23.

    Koivunen, P. et al. Inhibition of hypoxia-inducible factor (HIF) hydroxylases by citric acid cycle intermediates: possible links between cell metabolism and stabilization of HIF. J. Biol. Chem. 282, 4524–4532 (2007).

    CAS  PubMed  Google Scholar 

  24. 24.

    Hirsila, M., Koivunen, P., Gunzler, V., Kivirikko, K. I. & Myllyharju, J. Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor. J. Biol. Chem. 278, 30772–30780 (2003).

    PubMed  Google Scholar 

  25. 25.

    Cervera, A. M. et al. An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer Lett. 233, 131–138 (2006).

    CAS  PubMed  Google Scholar 

  26. 26.

    Tian, Y. M., Mole, D. R., Ratcliffe, P. J. & Gleadle, J. M. Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation. Biochem. J. 397, 179–186 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Yang, W. S., Campbell, M. & Chang, P. C. SUMO modification of a heterochromatin histone demethylase JMJD2A enables viral gene transactivation and viral replication. PLoS Pathog. 13, e1006216 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Bueno, M. T. & Richard, S. SUMOylation negatively modulates target gene occupancy of the KDM5B, a histone lysine demethylase. Epigenetics 8, 1162–1175 (2013).

    CAS  PubMed  Google Scholar 

  29. 29.

    Cheng, M. B. et al. Specific phosphorylation of histone demethylase KDM3A determines target gene expression in response to heat shock. PLoS Biol. 12, e1002026 (2014).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Jeong, J. J. et al. Cytokine-regulated phosphorylation and activation of TET2 by JAK2 in hematopoiesis. Cancer Discov. 9, 778–795 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Olsen, J. V. et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635–648 (2006).

    CAS  PubMed  Google Scholar 

  32. 32.

    Foxler, D. E. et al. The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. Nat. Cell Biol. 14, 201–208 (2012).

    CAS  PubMed  Google Scholar 

  33. 33.

    Zhang, C. S. et al. RHOBTB3 promotes proteasomal degradation of HIFα through facilitating hydroxylation and suppresses the Warburg effect. Cell Res. 25, 1025–1042 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Kaelin, W. G. Jr. The VHL tumor suppressor gene: insights into oxygen sensing and cancer. Trans. Am. Clin. Climatol. Assoc. 128, 298–307 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Lee, S. et al. Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8, 155–167 (2005).

    PubMed  Google Scholar 

  36. 36.

    Maxwell, P. H. A common pathway for genetic events leading to pheochromocytoma. Cancer Cell 8, 91–93 (2005).

    CAS  PubMed  Google Scholar 

  37. 37.

    Kondo, K., Kim, W. Y., Lechpammer, M. & Kaelin, W. G. Jr. Inhibition of HIF2α is sufficient to suppress pVHL-defective tumor growth. PLoS Biol. 1, E83 (2003).

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kondo, K., Klco, J., Nakamura, E., Lechpammer, M. & Kaelin, W. G. Jr. Inhibition of HIF is necessary for tumor suppression by the von Hippel–Lindau protein. Cancer Cell 1, 237–246 (2002).

    CAS  PubMed  Google Scholar 

  39. 39.

    Maranchie, J. K. et al. The contribution of VHL substrate binding and HIF1α to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 1, 247–255 (2002).

    CAS  PubMed  Google Scholar 

  40. 40.

    Raval, R. R. et al. Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel–Lindau-associated renal cell carcinoma. Mol. Cell Biol. 25, 5675–5686 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Shen, C. et al. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1, 222–235 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zimmer, M., Doucette, D., Siddiqui, N. & Iliopoulos, O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL–/– tumors. Mol. Cancer Res. 2, 89–95 (2004).

    CAS  PubMed  Google Scholar 

  43. 43.

    Gordan, J. D. et al. HIF-α effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 14, 435–446 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Dahia, P. L. Pheochromocytomas and paragangliomas, genetically diverse and minimalist, all at once! Cancer Cell 31, 159–161 (2017).

    CAS  PubMed  Google Scholar 

  45. 45.

    Ladroue, C. et al. PHD2 mutation and congenital erythrocytosis with paraganglioma. N. Engl. J. Med. 359, 2685–2692 (2008). This study identifies a novel germline mutation in EGLN1 that is associated with constitutive HIF activation, pseudo-hypoxic erythrocytosis and paraganglioma.

    CAS  PubMed  Google Scholar 

  46. 46.

    Yang, C. et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood 121, 2563–2566 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Zhuang, Z. et al. HIF2A gain-of-function mutations detected in duodenal gangliocytic paraganglioma. Endocr. Relat. Cancer 23, L13–L16 (2016).

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Fielding, J. W. et al. PHD2 inactivation in type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies. J. Physiol. https://doi.org/10.1113/JP275996 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Cockman, M. E. et al. Lack of activity of recombinant HIF prolyl hydroxylases (PHDs) on reported non-HIF substrates. eLife https://doi.org/10.7554/eLife.46490 (2019). This study comprehensively tests the ability of EGLN enzymes to hydroxylate a panel of putative non-HIF EGLN substrates using several experimental approaches and finds that none of the substrates is hydroxylated by EGLN enzymes in vitro. Although these negative results could be due to technical factors, they challenge the idea that these non-HIF proteins are authentic EGLN substrates in vivo.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Chen, N. et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N. Engl. J. Med. 381, 1011–1022 (2019).

    CAS  PubMed  Google Scholar 

  52. 52.

    Chen, N. et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N. Engl. J. Med. 381, 1001–1010 (2019).

    CAS  PubMed  Google Scholar 

  53. 53.

    Hammond, E. M. et al. The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin. Oncol. 26, 277–288 (2014).

    CAS  Google Scholar 

  54. 54.

    Dayan, F., Roux, D., Brahimi-Horn, M. C., Pouyssegur, J. & Mazure, N. M. The oxygen sensor factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bifunctional transcriptional character of hypoxia-inducible factor-1α. Cancer Res. 66, 3688–3698 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Lando, D. et al. FIH-1 is an asparaginyl hydroxylase enzyme that regulates the transcriptional activity of hypoxia-inducible factor. Genes Dev. 16, 1466–1471 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Mahon, P. C., Hirota, K. & Semenza, G. L. FIH-1: a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev. 15, 2675–2686 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Yang, M. et al. Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. FEBS J. 278, 1086–1097 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Cockman, M. E. et al. Posttranslational hydroxylation of ankyrin repeats in IκB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc. Natl Acad. Sci. USA 103, 14767–14772 (2006). This study identifies numerous ankyrin repeat proteins as non-HIF substrates of FIH and suggested that they indirectly influence the amount of FIH available to hydroxylate HIF.

    CAS  PubMed  Google Scholar 

  59. 59.

    Zhang, N. et al. The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism. Cell Metab. 11, 364–378 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Melvin, A. & Rocha, S. Chromatin as an oxygen sensor and active player in the hypoxia response. Cell Signal. 24, 35–43 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Lu, Y., Chu, A., Turker, M. S. & Glazer, P. M. Hypoxia-induced epigenetic regulation and silencing of the BRCA1 promoter. Mol. Cell Biol. 31, 3339–3350 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Chervona, Y. & Costa, M. The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals. Free. Radic. Biol. Med. 53, 1041–1047 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Chakraborty, A. A. et al. Histone demethylase KDM6A directly senses oxygen to control chromatin and cell fate. Science 363, 1217–1222 (2019). This study demonstrates that the H3K27 histone lysine demethylase KDM6A is an oxygen sensor and links this to the well-established ability of hypoxia to influence cellular differentiation.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Batie, M. et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science 363, 1222–1226 (2019). This study demonstrates that the H3K4 histone lysine demethylase KDM5A is an oxygen sensor.

    CAS  PubMed  Google Scholar 

  65. 65.

    Cascella, B. & Mirica, L. M. Kinetic analysis of iron-dependent histone demethylases: α-ketoglutarate substrate inhibition and potential relevance to the regulation of histone demethylation in cancer cells. Biochemistry 51, 8699–8701 (2012).

    CAS  PubMed  Google Scholar 

  66. 66.

    Hancock, R. L., Masson, N., Dunne, K., Flashman, E. & Kawamura, A. The activity of JmjC histone lysine demethylase KDM4A is highly sensitive to oxygen concentrations. ACS Chem. Biol. 12, 1011–1019 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Thienpont, B. et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537, 63–68 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Dai, B. et al. Histone demethylase KDM5A inhibits glioma cells migration and invasion by down regulating ZEB1. Biomed. Pharmacother. 99, 72–80 (2018).

    CAS  PubMed  Google Scholar 

  69. 69.

    Kong, S. Y., Kim, W., Lee, H. R. & Kim, H. J. The histone demethylase KDM5A is required for the repression of astrocytogenesis and regulated by the translational machinery in neural progenitor cells. FASEB J. 32, 1108–1119 (2018).

    CAS  PubMed  Google Scholar 

  70. 70.

    Andricovich, J. et al. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell 33, 512–526.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Ntziachristos, P. et al. Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 514, 513–517 (2014). This study demonstrates that the H3K27 histone lysine demethylase paralogues KDM6A and KDM6B have opposing functions in T-ALL.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Ivan, M. & Kaelin, W. G. Jr. The EGLN–HIF O2-sensing system: multiple inputs and feedbacks. Mol. Cell 66, 772–779 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Zhang, J. et al. Accumulation of succinate in cardiac ischemia primarily occurs via canonical Krebs cycle activity. Cell Rep. 23, 2617–2628 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Intlekofer, A. M. et al. Hypoxia induces production of l-2-hydroxyglutarate. Cell Metab. 22, 304–311 (2015). This study demonstrates that hypoxia indirectly inhibits the activity of numerous histone lysine demethylases by inducing the production of S-2HG.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Intlekofer, A. M. et al. l-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat. Chem. Biol. 13, 494–500 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Oldham, W. M., Clish, C. B., Yang, Y. & Loscalzo, J. Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab. 22, 291–303 (2015). This study demonstrates that cells mitigate the redox stress induced by hypoxia by producing a metabolite, S-2HG, that inhibits the electron transport chain and glycolysis.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Tyrakis, P. A. et al. S-2-Hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Masson, N. et al. Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants. Science 365, 65–69 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Akter, S. et al. Chemical proteomics reveals new targets of cysteine sulfinic acid reductase. Nat. Chem. Biol. 14, 995–1004 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Coffey, R. & Ganz, T. Iron homeostasis: an anthropocentric perspective. J. Biol. Chem. 292, 12727–12734 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Roy, C. N. & Andrews, N. C. Anemia of inflammation: the hepcidin link. Curr. Opin. Hematol. 12, 107–111 (2005).

    CAS  PubMed  Google Scholar 

  84. 84.

    Barman-Aksozen, J., Beguin, C., Dogar, A. M., Schneider-Yin, X. & Minder, E. I. Iron availability modulates aberrant splicing of ferrochelatase through the iron- and 2-oxoglutarate dependent dioxygenase Jmjd6 and U2AF65. Blood Cell Mol. Dis. 51, 151–161 (2013).

    CAS  Google Scholar 

  85. 85.

    Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Yamamoto, K. et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis 35, 2404–2414 (2014).

    CAS  PubMed  Google Scholar 

  88. 88.

    Yu, S. H. et al. JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML. Nat. Commun. 9, 3369 (2018).

    PubMed  PubMed Central  Google Scholar 

  89. 89.

    Cimmino, L. et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat. Immunol. 16, 653–662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Neri, F. et al. TET1 is a tumour suppressor that inhibits colon cancer growth by derepressing inhibitors of the WNT pathway. Oncogene 34, 4168–4176 (2015).

    CAS  PubMed  Google Scholar 

  91. 91.

    Wu, B. K. & Brenner, C. Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep. 9, 1827–1840 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095.e20 (2017). This study demonstrates that stimulation of TET activity by reducing agents reverses the leukaemogenic effects of TET2 loss, thereby providing a rationale for the use of ascorbate in patients with TET2-mutant haematopoietic malignancies.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Hirsila, M. et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 19, 1308–1310 (2005).

    CAS  PubMed  Google Scholar 

  95. 95.

    Li, Q., Ke, Q. & Costa, M. Alterations of histone modifications by cobalt compounds. Carcinogenesis 30, 1243–1251 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Kaczmarek, M. et al. The role of ascorbate in the modulation of HIF-1α protein and HIF-dependent transcription by chromiumVI and nickelII. Free. Radic. Biol. Med. 42, 1246–1257 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Kuiper, C. & Vissers, M. C. Ascorbate as a co-factor for Fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front. Oncol. 4, 359 (2014).

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Nytko, K. J. et al. Vitamin C is dispensable for oxygen sensing in vivo. Blood 117, 5485–5493 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Knowles, H. J., Raval, R. R., Harris, A. L. & Ratcliffe, P. J. Effect of ascorbate on the activity of hypoxia-inducible factor in cancer cells. Cancer Res. 63, 1764–1768 (2003).

    CAS  PubMed  Google Scholar 

  101. 101.

    Kuiper, C., Dachs, G. U., Currie, M. J. & Vissers, M. C. Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. Free. Radic. Biol. Med. 69, 308–317 (2014).

    CAS  PubMed  Google Scholar 

  102. 102.

    Campbell, E. J. et al. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo–/– mice. Cancer Med. 4, 303–314 (2015).

    CAS  PubMed  Google Scholar 

  103. 103.

    Gao, P. et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12, 230–238 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Agathocleous, M. et al. Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549, 476–481 (2017). This study demonstrates that ascorbate depletion phenocopies the leukaemogenic effects of TET2 loss, thereby reinforcing the in vivo role of reducing agents in maintaining 2OGDD activity.

    PubMed  PubMed Central  Google Scholar 

  105. 105.

    Shenoy, N. et al. Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. J. Clin. Invest. 129, 1612–1625 (2019).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Ge, G. et al. Restoration of 5-hydroxymethylcytosine by ascorbate blocks kidney tumour growth. EMBO Rep. https://doi.org/10.15252/embr.201745401 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Pritchard, J. B. Intracellular α-ketoglutarate controls the efficacy of renal organic anion transport. J. Pharmacol. Exp. Ther. 274, 1278–1284 (1995).

    CAS  PubMed  Google Scholar 

  108. 108.

    Olenchock, B. A. et al. EGLN1 inhibition and rerouting of α-ketoglutarate suffice for remote ischemic protection. Cell 165, 497 (2016).

    CAS  PubMed  Google Scholar 

  109. 109.

    Raffel, S. et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384–388 (2017).

    CAS  PubMed  Google Scholar 

  110. 110.

    Morris, J. P. T. et al. α-Ketoglutarate links p53 to cell fate during tumour suppression. Nature 573, 595–599 (2019). This study demonstrates that accumulation of intracellular 2OG stimulates the differentiation of p53-deficient tumour cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Yong, C., Stewart, G. D. & Frezza, C. Oncometabolites in renal cancer. Nat. Rev. Nephrol. 16, 156–172 (2020).

    CAS  PubMed  Google Scholar 

  112. 112.

    Jiang, Y. et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat. Cell Biol. 17, 1158–1168 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Yogev, O. et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 8, e1000328 (2010).

    PubMed  PubMed Central  Google Scholar 

  114. 114.

    Sulkowski, P. L. et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 582, 586–591 (2020).

    CAS  PubMed  Google Scholar 

  115. 115.

    Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 116.

    Carey, B. W., Finley, L. W., Cross, J. R., Allis, C. D. & Thompson, C. B. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature 518, 413–416 (2015). This study demonstrates that the intracellular 2OG to succinate ratio contributes to the maintenance of stem cell pluripotency.

    CAS  PubMed  Google Scholar 

  117. 117.

    TeSlaa, T. et al. α-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 24, 485–493 (2016). This study demonstrates that 2OG contributes to the differentiation of pluripotent stem cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Gimenez-Roqueplo, A. P. et al. The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of Complex II in the mitochondrial respiratory chain and activates the hypoxia pathway. Am. J. Hum. Genet. 69, 1186–1197 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Isaacs, J. S. et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 8, 143–153 (2005).

    CAS  PubMed  Google Scholar 

  121. 121.

    Pollard, P. J. et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum. Mol. Genet. 14, 2231–2239 (2005).

    CAS  PubMed  Google Scholar 

  122. 122.

    Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 7, 77–85 (2005). Together with Isaacs et al. (2005) and Pollard et al. (2005), this study shows that fumarate and succinate can inhibit EGLN enzymes and stabilize HIF.

    CAS  PubMed  Google Scholar 

  123. 123.

    Adam, J. et al. Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer Cell 20, 524–537 (2011). This study shows that deletion of HIF1 actually worsens the pathology of Fh1-deficient kidneys, underscoring the need for caution when inferring causality based purely on correlations.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).

    CAS  PubMed  Google Scholar 

  125. 125.

    Xiao, M. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev. 26, 1326–1338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Aspuria, P. P. et al. Succinate dehydrogenase inhibition leads to epithelial–mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab. 2, 21 (2014).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Struys, E. A. et al. Kinetic characterization of human hydroxyacid-oxoacid transhydrogenase: relevance to d-2-hydroxyglutaric and γ-hydroxybutyric acidurias. J. Inherit. Metab. Dis. 28, 921–930 (2005).

    CAS  PubMed  Google Scholar 

  128. 128.

    Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Losman, J. A. et al. (R)-2-Hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science 339, 1621–1625 (2013). This study shows that R-2HG acts as an oncometabolite at least in part by inhibiting TET2 and that its effects can be reversed in preclinical models. The latter finding has galvanized efforts to develop drugs that block 2-HG production by mutant IDH.

    CAS  PubMed  Google Scholar 

  130. 130.

    Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).

    CAS  PubMed  Google Scholar 

  131. 131.

    Yen, K. et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7, 478–493 (2017).

    CAS  PubMed  Google Scholar 

  132. 132.

    Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018).

    CAS  PubMed  Google Scholar 

  134. 134.

    Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Ito, S. et al. Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466, 1129–1133 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011). This study shows that R-2HG is able to inhibit specific 2OGDDs.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Koivunen, P. et al. Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation. Nature 483, 484–488 (2012). This study shows that R-2HG functions as a co-substrate to activate EGLN enzymes.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Madzo, J., Vasanthakumar, A. & Godley, L. A. Perturbations of 5-hydroxymethylcytosine patterning in hematologic malignancies. Semin. Hematol. 50, 61–69 (2013).

    CAS  PubMed  Google Scholar 

  141. 141.

    Kroeze, L. I. et al. Characterization of acute myeloid leukemia based on levels of global hydroxymethylation. Blood 124, 1110–1118 (2014).

    CAS  PubMed  Google Scholar 

  142. 142.

    Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010). This study shows that IDH and TET2 mutations are mutually exclusive in AML and that R-2HG acts as an oncometabolite at least in part by inhibiting TET2.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Xu, X. et al. KDM3B shows tumor-suppressive activity and transcriptionally regulates HOXA1 through retinoic acid response elements in acute myeloid leukemia. Leuk. Lymphoma 59, 204–213 (2018).

    CAS  PubMed  Google Scholar 

  144. 144.

    Choi, C. et al. 2-Hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 18, 624–629 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Longuespee, R. et al. Rapid detection of 2-hydroxyglutarate in frozen sections of IDH mutant tumors by MALDI-TOF mass spectrometry. Acta Neuropathol. Commun. 6, 21 (2018).

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    Jezek, P. 2-Hydroxyglutarate in cancer cells. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2019.7902 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Cleven, A. H. G. et al. IDH1 or -2 mutations do not predict outcome and do not cause loss of 5-hydroxymethylcytosine or altered histone modifications in central chondrosarcomas. Clin. Sarcoma Res. 7, 8 (2017).

    PubMed  PubMed Central  Google Scholar 

  148. 148.

    Kim, Y. H. et al. TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J. Clin. Pathol. 64, 850–852 (2011).

    CAS  PubMed  Google Scholar 

  149. 149.

    Chowdhury, R. et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 12, 463–469 (2011). This study shows that R-2HG is able to inhibit specific 2OGDDs.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Janke, R., Iavarone, A. T. & Rine, J. Oncometabolite d-2-hydroxyglutarate enhances gene silencing through inhibition of specific H3K36 histone demethylases. eLife https://doi.org/10.7554/eLife.22451 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Kernytsky, A. et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125, 296–303 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Sasaki, M. et al. d-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Turcan, S. et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat. Genet. 50, 62–72 (2018).

    CAS  PubMed  Google Scholar 

  157. 157.

    Williams, S. C. et al. R132H-mutation of isocitrate dehydrogenase-1 is not sufficient for HIF-1α upregulation in adult glioma. Acta Neuropathol. 121, 279–281 (2011).

    PubMed  Google Scholar 

  158. 158.

    Polivka, J. Jr. et al. IDH1 mutation is associated with lower expression of VEGF but not microvessel formation in glioblastoma multiforme. Oncotarget 9, 16462–16476 (2018).

    PubMed  PubMed Central  Google Scholar 

  159. 159.

    Bottcher, M. et al. d-2-Hydroxyglutarate interferes with HIF-1α stability skewing T-cell metabolism towards oxidative phosphorylation and impairing TH17 polarization. Oncoimmunology 7, e1445454 (2018).

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).

    CAS  PubMed  Google Scholar 

  161. 161.

    Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Rzem, R., Vincent, M. F., Van Schaftingen, E. & Veiga-da-Cunha, M. l-2-Hydroxyglutaric aciduria, a defect of metabolite repair. J. Inherit. Metab. Dis. 30, 681–689 (2007).

    CAS  PubMed  Google Scholar 

  163. 163.

    Munn, L. L. & Jain, R. K. Vascular regulation of antitumor immunity. Science 365, 544–545 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Damgaci, S. et al. Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology 154, 354–362 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Shim, E. H. et al. l-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    McBrayer, S. K. et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101–116.e25 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Tonjes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013).

    PubMed  PubMed Central  Google Scholar 

  168. 168.

    Benevolenskaya, E. V., Murray, H. L., Branton, P., Young, R. A. & Kaelin, W. G. Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol. Cell 18, 623–635 (2005).

    CAS  PubMed  Google Scholar 

  169. 169.

    McBrayer, S. K. et al. Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. Proc. Natl Acad. Sci. USA 115, E3741–E3748 (2018).

    CAS  PubMed  Google Scholar 

  170. 170.

    Lin, W. et al. Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1. Proc. Natl Acad. Sci. USA 108, 13379–13386 (2011).

    CAS  PubMed  Google Scholar 

  171. 171.

    Hinohara, K. et al. KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell 34, 939–953.e9 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Hou, J. et al. Genomic amplification and a role in drug-resistance for the KDM5A histone demethylase in breast cancer. Am. J. Transl Res. 4, 247–256 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Teng, Y. C. et al. Histone demethylase RBP2 promotes lung tumorigenesis and cancer metastasis. Cancer Res. 73, 4711–4721 (2013).

    CAS  PubMed  Google Scholar 

  175. 175.

    Liu, X. et al. KDM5B promotes drug resistance by regulating melanoma-propagating cell subpopulations. Mol. Cancer Ther. 18, 706–717 (2019).

    CAS  PubMed  Google Scholar 

  176. 176.

    Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Miyake, Y. et al. Identification of novel lysine demethylase 5-selective inhibitors by inhibitor-based fragment merging strategy. Bioorg Med. Chem. 27, 1119–1129 (2019).

    CAS  PubMed  Google Scholar 

  178. 178.

    Horton, J. R. et al. Structural basis for KDM5A histone lysine demethylase inhibition by diverse compounds. Cell Chem. Biol. 23, 769–781 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Johansson, C. et al. Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nat. Chem. Biol. 12, 539–545 (2016).

    CAS  PubMed  Google Scholar 

  180. 180.

    Van der Meulen, J. et al. The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 125, 13–21 (2015).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Benyoucef, A. et al. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev. 30, 508–521 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Kim, J. H. et al. UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. Cancer Res. 74, 1705–1717 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Berry, W. L., Shin, S., Lightfoot, S. A. & Janknecht, R. Oncogenic features of the JMJD2A histone demethylase in breast cancer. Int. J. Oncol. 41, 1701–1706 (2012).

    CAS  PubMed  Google Scholar 

  185. 185.

    Cheung, N. et al. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 29, 32–48 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Liu, G. et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28, 4491–4500 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Vinatzer, U. et al. Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin. Cancer Res. 14, 6426–6431 (2008).

    CAS  PubMed  Google Scholar 

  188. 188.

    Yang, Z. Q. et al. Identification of a novel gene, GASC1, within an amplicon at 9p23–24 frequently detected in esophageal cancer cell lines. Cancer Res. 60, 4735–4739 (2000).

    CAS  PubMed  Google Scholar 

  189. 189.

    Berry, W. L. & Janknecht, R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 73, 2936–2942 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Ye, Q. et al. Genetic alterations of KDM4 subfamily and therapeutic effect of novel demethylase inhibitor in breast cancer. Am. J. Cancer Res. 5, 1519–1530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Shin, S. & Janknecht, R. Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem. Biophys. Res. Commun. 359, 742–746 (2007).

    CAS  PubMed  Google Scholar 

  192. 192.

    Duan, L. et al. KDM4/JMJD2 histone demethylase inhibitors block prostate tumor growth by suppressing the expression of AR and BMYB-regulated genes. Chem. Biol. 22, 1185–1196 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. 193.

    Carter, D. M. et al. Identification of a novel benzimidazole pyrazolone scaffold that inhibits KDM4 lysine demethylases and reduces proliferation of prostate cancer cells. SLAS Discov. 22, 801–812 (2017).

    CAS  PubMed  Google Scholar 

  194. 194.

    Shih, A. H. et al. Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2- and TET2-mutant acute myeloid leukemia. Cancer Discov. 7, 494–505 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705–2712 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Jacobs, C., Hutton, B., Ng, T., Shorr, R. & Clemons, M. Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review. Oncologist 20, 210–223 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. 197.

    Ngo, B., Van Riper, J. M., Cantley, L. C. & Yun, J. Targeting cancer vulnerabilities with high-dose vitamin C. Nat. Rev. Cancer 19, 271–282 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Chen, Q. et al. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl Acad. Sci. USA 105, 11105–11109 (2008).

    CAS  PubMed  Google Scholar 

  199. 199.

    Qiu, B. & Simon, M. C. Oncogenes strike a balance between cellular growth and homeostasis. Semin. Cell Dev. Biol. 43, 3–10 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Nguyen, C. & Pandey, S. Exploiting mitochondrial vulnerabilities to trigger apoptosis selectively in cancer cells. Cancers https://doi.org/10.3390/cancers11070916 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  201. 201.

    Bjelakovic, G., Nikolova, D., Gluud, L. L., Simonetti, R. G. & Gluud, C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD007176.pub2 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Oser, M. G. et al. The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain neuroendocrine differentiation and promote small cell lung cancer tumorigenesis. Genes Dev. 33, 1718–1738 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 203.

    Chakraborty, A. A. et al. HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aal5272 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Shpargel, K. B., Sengoku, T., Yokoyama, S. & Magnuson, T. UTX and UTY demonstrate histone demethylase-independent function in mouse embryonic development. PLoS Genet. 8, e1002964 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 (2007).

    CAS  PubMed  Google Scholar 

  206. 206.

    Celik, H. et al. JARID2 functions as a tumor suppressor in myeloid neoplasms by repressing self-renewal in hematopoietic progenitor cells. Cancer Cell 34, 741–756.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 207.

    Frescas, D., Guardavaccaro, D., Bassermann, F., Koyama-Nasu, R. & Pagano, M. JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes. Nature 450, 309–313 (2007).

    CAS  PubMed  Google Scholar 

  208. 208.

    Hu, Z. et al. A novel nuclear protein, 5qNCA (LOC51780) is a candidate for the myeloid leukemia tumor suppressor gene on chromosome 5 band q31. Oncogene 20, 6946–6954 (2001).

    CAS  PubMed  Google Scholar 

  209. 209.

    van Zutven, L. J. et al. Identification of NUP98 abnormalities in acute leukemia: JARID1A (12p13) as a new partner gene. Genes Chromosomes Cancer 45, 437–446 (2006).

    PubMed  Google Scholar 

  210. 210.

    Wong, S. H. et al. The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 28, 198–209 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. 211.

    Rondinelli, B. et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J. Clin. Invest. 125, 4625–4637 (2015).

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Shen, H. et al. Suppression of enhancer overactivation by a RACK7–histone demethylase complex. Cell 165, 331–342 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. 213.

    Zhan, D. et al. Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia. Leuk. Res. 65, 20–24 (2018).

    CAS  PubMed  Google Scholar 

  214. 214.

    De Keersmaecker, K. et al. Exome sequencing identifies mutation in CNOT3 and ribosomal genes RPL5 and RPL10 in T-cell acute lymphoblastic leukemia. Nat. Genet. 45, 186–190 (2013).

    PubMed  PubMed Central  Google Scholar 

  215. 215.

    Park, J. L. et al. Decrease of 5hmC in gastric cancers is associated with TET1 silencing due to with DNA methylation and bivalent histone marks at TET1 CpG island 3′-shore. Oncotarget 6, 37647–37662 (2015).

    PubMed  PubMed Central  Google Scholar 

  216. 216.

    Nickerson, M. L. et al. TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene 36, 2172–2183 (2017).

    CAS  PubMed  Google Scholar 

  217. 217.

    Lavaissiere, L. et al. Overexpression of human aspartyl(asparaginyl)β-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J. Clin. Invest. 98, 1313–1323 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218.

    Dong, X. et al. Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype. Oncotarget 6, 1231–1248 (2015).

    PubMed  Google Scholar 

  219. 219.

    Zou, Q. et al. Hydroxylase activity of ASPH promotes hepatocellular carcinoma metastasis through epithelial-to-mesenchymal transition pathway. EBioMedicine 31, 287–298 (2018).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Li, Z. et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell 31, 127–141 (2017).

    PubMed  PubMed Central  Google Scholar 

  221. 221.

    Zou, D. et al. The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int. 19, 321 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. 222.

    Lei, X. et al. JARID2 promotes invasion and metastasis of hepatocellular carcinoma by facilitating epithelial–mesenchymal transition through PTEN/AKT signaling. Oncotarget 7, 40266–40284 (2016).

    PubMed  PubMed Central  Google Scholar 

  223. 223.

    Zhu, X. X. et al. Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer. Oncotarget 8, 24483–24490 (2017).

    PubMed  PubMed Central  Google Scholar 

  224. 224.

    Aprelikova, O. et al. The epigenetic modifier JMJD6 is amplified in mammary tumors and cooperates with c-Myc to enhance cellular transformation, tumor progression, and metastasis. Clin. Epigenetics 8, 38 (2016).

    PubMed  PubMed Central  Google Scholar 

  225. 225.

    Wong, M. et al. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nat. Commun. 10, 3319 (2019).

    PubMed  PubMed Central  Google Scholar 

  226. 226.

    Liu, H., Liu, L., Holowatyj, A., Jiang, Y. & Yang, Z. Q. Integrated genomic and functional analyses of histone demethylases identify oncogenic KDM2A isoform in breast cancer. Mol. Carcinog. 55, 977–990 (2016).

    CAS  PubMed  Google Scholar 

  227. 227.

    Wagner, K. W. et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J. Clin. Invest. 123, 5231–5246 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 228.

    Banito, A. et al. The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma. Cancer Cell 33, 527–541.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. 229.

    Tzatsos, A. et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123, 727–739 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    Chen, M. et al. JMJD1C is required for the survival of acute myeloid leukemia by functioning as a coactivator for key transcription factors. Genes Dev. 29, 2123–2139 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. 231.

    Zhu, N. et al. MLL-AF9- and HOXA9-mediated acute myeloid leukemia stem cell self-renewal requires JMJD1C. J. Clin. Invest. 126, 997–1011 (2016).

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Black, J. C. et al. KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell 154, 541–555 (2013).

    CAS  PubMed  Google Scholar 

  233. 233.

    Guerra-Calderas, L., Gonzalez-Barrios, R., Herrera, L. A., Cantu de Leon, D. & Soto-Reyes, E. The role of the histone demethylase KDM4A in cancer. Cancer Genet. 208, 215–224 (2015).

    CAS  PubMed  Google Scholar 

  234. 234.

    Wilson, C. et al. The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 36, 2565–2576 (2017).

    CAS  PubMed  Google Scholar 

  235. 235.

    Wu, M. C. et al. KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis. Cell Death Dis. 10, 68 (2019).

    PubMed  PubMed Central  Google Scholar 

  236. 236.

    Yamamoto, S. et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25, 762–777 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. 237.

    Paolicchi, E., Crea, F., Farrar, W. L., Green, J. E. & Danesi, R. Histone lysine demethylases in breast cancer. Crit. Rev. Oncol. Hematol. 86, 97–103 (2013).

    PubMed  Google Scholar 

  238. 238.

    Xie, G. et al. UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor. Oncogene 36, 5497–5511 (2017).

    CAS  PubMed  Google Scholar 

  239. 239.

    Mallaney, C. et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia 33, 2506–2521 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 240.

    Wei, Y. et al. Global H3K4me3 genome mapping reveals alterations of innate immunity signaling and overexpression of JMJD3 in human myelodysplastic syndrome CD34+ cells. Leukemia 27, 2177–2186 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. 241.

    Bjorkman, M. et al. Systematic knockdown of epigenetic enzymes identifies a novel histone demethylase PHF8 overexpressed in prostate cancer with an impact on cell proliferation, migration and invasion. Oncogene 31, 3444–3456 (2012).

    CAS  PubMed  Google Scholar 

  242. 242.

    Shen, Y., Pan, X. & Zhao, H. The histone demethylase PHF8 is an oncogenic protein in human non-small cell lung cancer. Biochem. Biophys. Res. Commun. 451, 119–125 (2014).

    CAS  PubMed  Google Scholar 

  243. 243.

    Wang, Q. et al. Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. J. Clin. Invest. 126, 2205–2220 (2016).

    PubMed  PubMed Central  Google Scholar 

  244. 244.

    Huang, M. Y., Xuan, F., Liu, W. & Cui, H. J. MINA controls proliferation and tumorigenesis of glioblastoma by epigenetically regulating cyclins and CDKs via H3K9me3 demethylation. Oncogene 36, 387–396 (2017).

    CAS  PubMed  Google Scholar 

  245. 245.

    Lu, Y. et al. Lung cancer-associated JmjC domain protein mdig suppresses formation of tri-methyl lysine 9 of histone H3. Cell Cycle 8, 2101–2109 (2009).

    CAS  PubMed  Google Scholar 

  246. 246.

    Wang, P. et al. Oncometabolite d-2-hydroxyglutarate inhibits ALKBH DNA repair enzymes and sensitizes IDH mutant cells to alkylating agents. Cell Rep. 13, 2353–2361 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. 247.

    Lindstedt, G., Lindstedt, S. & Nordin, I. γ-Butyrobetaine hydroxylase in human kidney. Scand. J. Clin. Lab. Invest. 42, 477–485 (1982).

    CAS  PubMed  Google Scholar 

  248. 248.

    Lindstedt, S. & Nordin, I. Multiple forms of γ-butyrobetaine hydroxylase (EC 1.14.11.1). Biochem. J. 223, 119–127 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. 249.

    Tarhonskaya, H. et al. Investigating the contribution of the active site environment to the slow reaction of hypoxia-inducible factor prolyl hydroxylase domain 2 with oxygen. Biochem. J. 463, 363–372 (2014).

    CAS  PubMed  Google Scholar 

  250. 250.

    Ehrismann, D. et al. Studies on the activity of the hypoxia-inducible-factor hydroxylases using an oxygen consumption assay. Biochem. J. 401, 227–234 (2007).

    CAS  PubMed  Google Scholar 

  251. 251.

    Koivunen, P., Hirsila, M., Gunzler, V., Kivirikko, K. I. & Myllyharju, J. Catalytic properties of the asparaginyl hydroxylase (FIH) in the oxygen sensing pathway are distinct from those of its prolyl 4-hydroxylases. J. Biol. Chem. 279, 9899–9904 (2004).

    CAS  PubMed  Google Scholar 

  252. 252.

    Tarhonskaya, H. et al. Kinetic investigations of the role of factor inhibiting hypoxia-inducible factor (FIH) as an oxygen sensor. J. Biol. Chem. 290, 19726–19742 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. 253.

    Carbonneau, M. et al. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat. Commun. 7, 12700 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. 254.

    Upadhyay, A. K. et al. An analog of BIX-01294 selectively inhibits a family of histone H3 lysine 9 Jumonji demethylases. J. Mol. Biol. 416, 319–327 (2012).

    CAS  PubMed  Google Scholar 

  255. 255.

    Walport, L. J. et al. Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J. Biol. Chem. 289, 18302–18313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. 256.

    Myllyharju, J. & Kivirikko, K. I. Characterization of the iron- and 2-oxoglutarate-binding sites of human prolyl 4-hydroxylase. EMBO J. 16, 1173–1180 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. 257.

    Majamaa, K., Hanauske-Abel, H. M., Gunzler, V. & Kivirikko, K. I. The 2-oxoglutarate binding site of prolyl 4-hydroxylase. Identification of distinct subsites and evidence for 2-oxoglutarate decarboxylation in a ligand reaction at the enzyme-bound ferrous ion. Eur. J. Biochem. 138, 239–245 (1984).

    CAS  PubMed  Google Scholar 

  258. 258.

    Jansen, G. A. et al. Characterization of phytanoyl-Coenzyme A hydroxylase in human liver and activity measurements in patients with peroxisomal disorders. Clin. Chim. Acta 271, 203–211 (1998).

    CAS  PubMed  Google Scholar 

  259. 259.

    Mukherji, M. et al. Structure–function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum’s disease. Hum. Mol. Genet. 10, 1971–1982 (2001).

    CAS  PubMed  Google Scholar 

  260. 260.

    Passoja, K., Rautavuoma, K., Ala-Kokko, L., Kosonen, T. & Kivirikko, K. I. Cloning and characterization of a third human lysyl hydroxylase isoform. Proc. Natl Acad. Sci. USA 95, 10482–10486 (1998).

    CAS  PubMed  Google Scholar 

  261. 261.

    Sengoku, T. & Yokoyama, S. Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A. Genes Dev. 25, 2266–2277 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. 262.

    Jones, S. E., Olsen, L. & Gajhede, M. Structural basis of histone demethylase KDM6B histone 3 lysine 27 specificity. Biochemistry 57, 585–592 (2018).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Academy of Finland grants 266719 and 308009 and grants from the S. Jusélius Foundation, the Finnish Cancer Organization and the Jane and Aatos Erkko Foundation to P.K. J.-A.L. is supported by the NIH. W.G.K. is a Howard Hughes Medical Investigator and supported by the NIH.

Author information

Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to William G. Kaelin Jr..

Ethics declarations

Competing interests

W.G.K. Jr. declares the following competing interests: Lilly Pharmaceuticals (board of directors), Agios Pharmaceuticals (scientific advisory board), Cedilla Therapeutics (founder), Fibrogen (scientific advisory board, royalties), Nextech Invest (scientific advisory board, carried interest) and Tango Therapeutics (founder). J.-A.L. and P.K. declare no competing interests.

Additional information

Peer review information

Nature Reviews Cancer thanks M. Ashcroft, C. Simon and M. Vissers for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

DepMap: https://depmap.org/portal/

NCBI protein database: https://www.ncbi.nlm.nih.gov/protein

RCSB protein databank: https://www.rcsb.org/

Glossary

Enantiomer

One of two molecules that have the same atomic formula and the same sequence of atomic bonds but that differ in their 3D orientations insofar as they are mirror images of each other.

Hypoxia

A deficiency in the amount of oxygen being supplied to body tissues.

Oncometabolites

Intermediates of metabolism that abnormally accumulate in cancer cells and that promote tumorigenesis.

Bidentate

A bidentate ligand is a base that donates two pairs of electrons to a metal atom.

Hypoxaemia

A state in which the level of oxygen in the blood is lower than normal.

K m

(Michaelis constant). The substrate concentration required for an enzymatic reaction to achieve one-half of its maximum velocity in vitro; a high Km value indicates low affinity and a low Km value indicates high affinity.

IC50

(Half-maximal inhibitory concentration). The concentration at which an inhibitor half-maximally inhibits a biochemical reaction in vitro.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Losman, JA., Koivunen, P. & Kaelin, W.G. 2-Oxoglutarate-dependent dioxygenases in cancer. Nat Rev Cancer 20, 710–726 (2020). https://doi.org/10.1038/s41568-020-00303-3

Download citation

Search

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing