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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
DeBerardinis, R. J. & Chandel, N. S. We need to talk about the Warburg effect. Nat. Metab. 2, 127–129 (2020).
Baylin, S. B. & Jones, P. A. Epigenetic determinants of cancer. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a019505 (2016).
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).
Schmidt, C., Sciacovelli, M. & Frezza, C. Fumarate hydratase in cancer: a multifaceted tumour suppressor. Semin. Cell Dev. Biol. 98, 15–25 (2020).
Gill, A. J. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology 72, 106–116 (2018).
Dang, L., Yen, K. & Attar, E. C. IDH mutations in cancer and progress toward development of targeted therapeutics. Ann. Oncol. 27, 599–608 (2016).
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).
Kim, K. H. & Roberts, C. W. Targeting EZH2 in cancer. Nat. Med. 22, 128–134 (2016).
Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).
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).
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).
Wang, L. & Shilatifard, A. UTX mutations in human cancer. Cancer Cell 35, 168–176 (2019).
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).
Herr, C. Q. & Hausinger, R. P. Amazing diversity in biochemical roles of FeII/2-oxoglutarate oxygenases. Trends Biochem. Sci. 43, 517–532 (2018).
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).
Schofield, C. J. & Ratcliffe, P. J. Oxygen sensing by HIF hydroxylases. Nat. Rev. Mol. Cell Biol. 5, 343–354 (2004).
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.
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.
Briggs, K. J. et al. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine. Cell 166, 126–139 (2016).
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).
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.
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.
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).
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).
Cervera, A. M. et al. An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer Lett. 233, 131–138 (2006).
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).
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).
Bueno, M. T. & Richard, S. SUMOylation negatively modulates target gene occupancy of the KDM5B, a histone lysine demethylase. Epigenetics 8, 1162–1175 (2013).
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).
Jeong, J. J. et al. Cytokine-regulated phosphorylation and activation of TET2 by JAK2 in hematopoiesis. Cancer Discov. 9, 778–795 (2019).
Olsen, J. V. et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell 127, 635–648 (2006).
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).
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).
Kaelin, W. G. Jr. The VHL tumor suppressor gene: insights into oxygen sensing and cancer. Trans. Am. Clin. Climatol. Assoc. 128, 298–307 (2017).
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).
Maxwell, P. H. A common pathway for genetic events leading to pheochromocytoma. Cancer Cell 8, 91–93 (2005).
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).
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).
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).
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).
Shen, C. et al. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1, 222–235 (2011).
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).
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).
Dahia, P. L. Pheochromocytomas and paragangliomas, genetically diverse and minimalist, all at once! Cancer Cell 31, 159–161 (2017).
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.
Yang, C. et al. Novel HIF2A mutations disrupt oxygen sensing, leading to polycythemia, paragangliomas, and somatostatinomas. Blood 121, 2563–2566 (2013).
Zhuang, Z. et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N. Engl. J. Med. 367, 922–930 (2012).
Zhuang, Z. et al. HIF2A gain-of-function mutations detected in duodenal gangliocytic paraganglioma. Endocr. Relat. Cancer 23, L13–L16 (2016).
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).
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.
Chen, N. et al. Roxadustat treatment for anemia in patients undergoing long-term dialysis. N. Engl. J. Med. 381, 1011–1022 (2019).
Chen, N. et al. Roxadustat for anemia in patients with kidney disease not receiving dialysis. N. Engl. J. Med. 381, 1001–1010 (2019).
Hammond, E. M. et al. The meaning, measurement and modification of hypoxia in the laboratory and the clinic. Clin. Oncol. 26, 277–288 (2014).
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).
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).
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).
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).
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.
Zhang, N. et al. The asparaginyl hydroxylase factor inhibiting HIF-1α is an essential regulator of metabolism. Cell Metab. 11, 364–378 (2010).
Melvin, A. & Rocha, S. Chromatin as an oxygen sensor and active player in the hypoxia response. Cell Signal. 24, 35–43 (2012).
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).
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).
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.
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.
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).
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).
Thienpont, B. et al. Tumour hypoxia causes DNA hypermethylation by reducing TET activity. Nature 537, 63–68 (2016).
Dai, B. et al. Histone demethylase KDM5A inhibits glioma cells migration and invasion by down regulating ZEB1. Biomed. Pharmacother. 99, 72–80 (2018).
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).
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).
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).
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.
Ivan, M. & Kaelin, W. G. Jr. The EGLN–HIF O2-sensing system: multiple inputs and feedbacks. Mol. Cell 66, 772–779 (2017).
Chouchani, E. T. et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 515, 431–435 (2014).
Zhang, J. et al. Accumulation of succinate in cardiac ischemia primarily occurs via canonical Krebs cycle activity. Cell Rep. 23, 2617–2628 (2018).
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.
Intlekofer, A. M. et al. l-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat. Chem. Biol. 13, 494–500 (2017).
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.
Tyrakis, P. A. et al. S-2-Hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016).
Masson, N. et al. Conserved N-terminal cysteine dioxygenases transduce responses to hypoxia in animals and plants. Science 365, 65–69 (2019).
Akter, S. et al. Chemical proteomics reveals new targets of cysteine sulfinic acid reductase. Nat. Chem. Biol. 14, 995–1004 (2018).
Coffey, R. & Ganz, T. Iron homeostasis: an anthropocentric perspective. J. Biol. Chem. 292, 12727–12734 (2017).
Roy, C. N. & Andrews, N. C. Anemia of inflammation: the hepcidin link. Curr. Opin. Hematol. 12, 107–111 (2005).
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).
Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).
Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).
Yamamoto, K. et al. Loss of histone demethylase KDM6B enhances aggressiveness of pancreatic cancer through downregulation of C/EBPα. Carcinogenesis 35, 2404–2414 (2014).
Yu, S. H. et al. JMJD3 facilitates C/EBPβ-centered transcriptional program to exert oncorepressor activity in AML. Nat. Commun. 9, 3369 (2018).
Cimmino, L. et al. TET1 is a tumor suppressor of hematopoietic malignancy. Nat. Immunol. 16, 653–662 (2015).
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).
Wu, B. K. & Brenner, C. Suppression of TET1-dependent DNA demethylation is essential for KRAS-mediated transformation. Cell Rep. 9, 1827–1840 (2014).
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.
Moran-Crusio, K. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 20, 11–24 (2011).
Hirsila, M. et al. Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 19, 1308–1310 (2005).
Li, Q., Ke, Q. & Costa, M. Alterations of histone modifications by cobalt compounds. Carcinogenesis 30, 1243–1251 (2009).
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).
Sabharwal, S. S. & Schumacker, P. T. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat. Rev. Cancer 14, 709–721 (2014).
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).
Nytko, K. J. et al. Vitamin C is dispensable for oxygen sensing in vivo. Blood 117, 5485–5493 (2011).
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).
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).
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).
Gao, P. et al. HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12, 230–238 (2007).
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.
Shenoy, N. et al. Ascorbic acid-induced TET activation mitigates adverse hydroxymethylcytosine loss in renal cell carcinoma. J. Clin. Invest. 129, 1612–1625 (2019).
Ge, G. et al. Restoration of 5-hydroxymethylcytosine by ascorbate blocks kidney tumour growth. EMBO Rep. https://doi.org/10.15252/embr.201745401 (2018).
Pritchard, J. B. Intracellular α-ketoglutarate controls the efficacy of renal organic anion transport. J. Pharmacol. Exp. Ther. 274, 1278–1284 (1995).
Olenchock, B. A. et al. EGLN1 inhibition and rerouting of α-ketoglutarate suffice for remote ischemic protection. Cell 165, 497 (2016).
Raffel, S. et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature 551, 384–388 (2017).
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.
Yong, C., Stewart, G. D. & Frezza, C. Oncometabolites in renal cancer. Nat. Rev. Nephrol. 16, 156–172 (2020).
Jiang, Y. et al. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nat. Cell Biol. 17, 1158–1168 (2015).
Yogev, O. et al. Fumarase: a mitochondrial metabolic enzyme and a cytosolic/nuclear component of the DNA damage response. PLoS Biol. 8, e1000328 (2010).
Sulkowski, P. L. et al. Oncometabolites suppress DNA repair by disrupting local chromatin signalling. Nature 582, 586–591 (2020).
Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).
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.
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.
Wu, H. et al. Dual functions of Tet1 in transcriptional regulation in mouse embryonic stem cells. Nature 473, 389–393 (2011).
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).
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).
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).
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.
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.
Letouze, E. et al. SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell 23, 739–752 (2013).
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).
Aspuria, P. P. et al. Succinate dehydrogenase inhibition leads to epithelial–mesenchymal transition and reprogrammed carbon metabolism. Cancer Metab. 2, 21 (2014).
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).
Dang, L. et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744 (2009).
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.
Wang, F. et al. Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science 340, 622–626 (2013).
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).
Stein, E. M. et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 130, 722–731 (2017).
DiNardo, C. D. et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl. J. Med. 378, 2386–2398 (2018).
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).
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).
He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).
Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).
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.
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.
Madzo, J., Vasanthakumar, A. & Godley, L. A. Perturbations of 5-hydroxymethylcytosine patterning in hematologic malignancies. Semin. Hematol. 50, 61–69 (2013).
Kroeze, L. I. et al. Characterization of acute myeloid leukemia based on levels of global hydroxymethylation. Blood 124, 1110–1118 (2014).
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.
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).
Choi, C. et al. 2-Hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat. Med. 18, 624–629 (2012).
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).
Jezek, P. 2-Hydroxyglutarate in cancer cells. Antioxid. Redox Signal. https://doi.org/10.1089/ars.2019.7902 (2020).
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).
Kim, Y. H. et al. TET2 promoter methylation in low-grade diffuse gliomas lacking IDH1/2 mutations. J. Clin. Pathol. 64, 850–852 (2011).
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.
Lu, C. et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483, 474–478 (2012).
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).
Kernytsky, A. et al. IDH2 mutation-induced histone and DNA hypermethylation is progressively reversed by small-molecule inhibition. Blood 125, 296–303 (2015).
Sasaki, M. et al. d-2-Hydroxyglutarate produced by mutant IDH1 perturbs collagen maturation and basement membrane function. Genes Dev. 26, 2038–2049 (2012).
Sasaki, M. et al. IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488, 656–659 (2012).
Turcan, S. et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483, 479–483 (2012).
Turcan, S. et al. Mutant-IDH1-dependent chromatin state reprogramming, reversibility, and persistence. Nat. Genet. 50, 62–72 (2018).
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).
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).
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).
Blouw, B. et al. The hypoxic response of tumors is dependent on their microenvironment. Cancer Cell 4, 133–146 (2003).
Tarhonskaya, H. et al. Non-enzymatic chemistry enables 2-hydroxyglutarate-mediated activation of 2-oxoglutarate oxygenases. Nat. Commun. 5, 3423 (2014).
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).
Munn, L. L. & Jain, R. K. Vascular regulation of antitumor immunity. Science 365, 544–545 (2019).
Damgaci, S. et al. Hypoxia and acidosis: immune suppressors and therapeutic targets. Immunology 154, 354–362 (2018).
Shim, E. H. et al. l-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 4, 1290–1298 (2014).
McBrayer, S. K. et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101–116.e25 (2018).
Tonjes, M. et al. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1. Nat. Med. 19, 901–908 (2013).
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).
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).
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).
Hinohara, K. et al. KDM5 histone demethylase activity links cellular transcriptomic heterogeneity to therapeutic resistance. Cancer Cell 34, 939–953.e9 (2018).
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).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Teng, Y. C. et al. Histone demethylase RBP2 promotes lung tumorigenesis and cancer metastasis. Cancer Res. 73, 4711–4721 (2013).
Liu, X. et al. KDM5B promotes drug resistance by regulating melanoma-propagating cell subpopulations. Mol. Cancer Ther. 18, 706–717 (2019).
Roesch, A. et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141, 583–594 (2010).
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).
Horton, J. R. et al. Structural basis for KDM5A histone lysine demethylase inhibition by diverse compounds. Cell Chem. Biol. 23, 769–781 (2016).
Johansson, C. et al. Structural analysis of human KDM5B guides histone demethylase inhibitor development. Nat. Chem. Biol. 12, 539–545 (2016).
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).
Benyoucef, A. et al. UTX inhibition as selective epigenetic therapy against TAL1-driven T-cell acute lymphoblastic leukemia. Genes Dev. 30, 508–521 (2016).
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).
Hashizume, R. et al. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat. Med. 20, 1394–1396 (2014).
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).
Cheung, N. et al. Targeting aberrant epigenetic networks mediated by PRMT1 and KDM4C in acute myeloid leukemia. Cancer Cell 29, 32–48 (2016).
Liu, G. et al. Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. Oncogene 28, 4491–4500 (2009).
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).
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).
Berry, W. L. & Janknecht, R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 73, 2936–2942 (2013).
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).
Shin, S. & Janknecht, R. Activation of androgen receptor by histone demethylases JMJD2A and JMJD2D. Biochem. Biophys. Res. Commun. 359, 742–746 (2007).
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).
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).
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).
Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705–2712 (2014).
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).
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).
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).
Qiu, B. & Simon, M. C. Oncogenes strike a balance between cellular growth and homeostasis. Semin. Cell Dev. Biol. 43, 3–10 (2015).
Nguyen, C. & Pandey, S. Exploiting mitochondrial vulnerabilities to trigger apoptosis selectively in cancer cells. Cancers https://doi.org/10.3390/cancers11070916 (2019).
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).
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).
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).
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).
Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 (2007).
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).
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).
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).
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).
Wong, S. H. et al. The H3K4-methyl epigenome regulates leukemia stem cell oncogenic potential. Cancer Cell 28, 198–209 (2015).
Rondinelli, B. et al. Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. J. Clin. Invest. 125, 4625–4637 (2015).
Shen, H. et al. Suppression of enhancer overactivation by a RACK7–histone demethylase complex. Cell 165, 331–342 (2016).
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).
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).
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).
Nickerson, M. L. et al. TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene 36, 2172–2183 (2017).
Lavaissiere, L. et al. Overexpression of human aspartyl(asparaginyl)β-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J. Clin. Invest. 98, 1313–1323 (1996).
Dong, X. et al. Aspartate β-hydroxylase expression promotes a malignant pancreatic cellular phenotype. Oncotarget 6, 1231–1248 (2015).
Zou, Q. et al. Hydroxylase activity of ASPH promotes hepatocellular carcinoma metastasis through epithelial-to-mesenchymal transition pathway. EBioMedicine 31, 287–298 (2018).
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).
Zou, D. et al. The m6A eraser FTO facilitates proliferation and migration of human cervical cancer cells. Cancer Cell Int. 19, 321 (2019).
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).
Zhu, X. X. et al. Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer. Oncotarget 8, 24483–24490 (2017).
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).
Wong, M. et al. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nat. Commun. 10, 3319 (2019).
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).
Wagner, K. W. et al. KDM2A promotes lung tumorigenesis by epigenetically enhancing ERK1/2 signaling. J. Clin. Invest. 123, 5231–5246 (2013).
Banito, A. et al. The SS18-SSX oncoprotein hijacks KDM2B-PRC1.1 to drive synovial sarcoma. Cancer Cell 33, 527–541.e8 (2018).
Tzatsos, A. et al. KDM2B promotes pancreatic cancer via Polycomb-dependent and -independent transcriptional programs. J. Clin. Invest. 123, 727–739 (2013).
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).
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).
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).
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).
Wilson, C. et al. The histone demethylase KDM4B regulates peritoneal seeding of ovarian cancer. Oncogene 36, 2565–2576 (2017).
Wu, M. C. et al. KDM4B is a coactivator of c-Jun and involved in gastric carcinogenesis. Cell Death Dis. 10, 68 (2019).
Yamamoto, S. et al. JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25, 762–777 (2014).
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).
Xie, G. et al. UTX promotes hormonally responsive breast carcinogenesis through feed-forward transcription regulation with estrogen receptor. Oncogene 36, 5497–5511 (2017).
Mallaney, C. et al. Kdm6b regulates context-dependent hematopoietic stem cell self-renewal and leukemogenesis. Leukemia 33, 2506–2521 (2019).
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).
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).
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).
Wang, Q. et al. Stabilization of histone demethylase PHF8 by USP7 promotes breast carcinogenesis. J. Clin. Invest. 126, 2205–2220 (2016).
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).
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).
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).
Lindstedt, G., Lindstedt, S. & Nordin, I. γ-Butyrobetaine hydroxylase in human kidney. Scand. J. Clin. Lab. Invest. 42, 477–485 (1982).
Lindstedt, S. & Nordin, I. Multiple forms of γ-butyrobetaine hydroxylase (EC 1.14.11.1). Biochem. J. 223, 119–127 (1984).
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).
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).
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).
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).
Carbonneau, M. et al. The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway. Nat. Commun. 7, 12700 (2016).
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).
Walport, L. J. et al. Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J. Biol. Chem. 289, 18302–18313 (2014).
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).
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).
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).
Mukherji, M. et al. Structure–function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum’s disease. Hum. Mol. Genet. 10, 1971–1982 (2001).
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).
Sengoku, T. & Yokoyama, S. Structural basis for histone H3 Lys 27 demethylation by UTX/KDM6A. Genes Dev. 25, 2266–2277 (2011).
Jones, S. E., Olsen, L. & Gajhede, M. Structural basis of histone demethylase KDM6B histone 3 lysine 27 specificity. Biochemistry 57, 585–592 (2018).
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
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
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.
- Km
-
(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
About this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41568-020-00303-3
This article is cited by
-
Monocarboxylate transporters facilitate succinate uptake into brown adipocytes
Nature Metabolism (2024)
-
A homoeostatic switch causing glycerol-3-phosphate and phosphoethanolamine accumulation triggers senescence by rewiring lipid metabolism
Nature Metabolism (2024)
-
Systematic analysis of integrated bioinformatics to identify upregulated THBS2 expression in colorectal cancer cells inhibiting tumour immunity through the HIF1A/Lactic Acid/GPR132 pathway
Cancer Cell International (2023)
-
Inhibition of fatty acid oxidation enables heart regeneration in adult mice
Nature (2023)
-
Hypoxia switches TET1 from being tumor-suppressive to oncogenic
Oncogene (2023)
