Regulation of the 2-oxoglutarate-dependent dioxygenases and implications for cancer
Abstract
There is growing interest in the family of 2-OG (2-oxoglutarate)-dependent dioxygenase enzymes that catalyse the hydroxylation of a wide range of organic targets. Members of this family that regulate the cell's hypoxic response and epigenetic processes, particularly the demethylation of histones and DNA, have been identified in mammalian cells. The dependence of these enzymes on molecular oxygen and 2-OG as obligatory substrates, together with their need for iron and ascorbate as cofactors, has implications for their role as metabolic sensors. The oxygen-sensing property is utilized by the hydroxylases that regulate hypoxia-inducible factor and this has been well characterized, particularly with respect to tumour biology. However, the potential for metabolic sensing more generally is also of interest, and future research will expand our understanding of the effect of mitochondrial viability and nutrient (iron and ascorbate) supply on 2-OG-dependent dioxygenase activity.
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Vitamin C regulates the stabilization and activation of the hypoxia-inducible factor (HIF)-1 through the stimulation of regulatory hydroxylases.
“Through the stimulation of regulatory hydroxylases, vitamin C also regulates the stabilization and activation of the hypoxia-inducible factor (HIF)-1, a metabolic sensor that controls the expression of hundreds of genes involved with cell survival and tissue remodelling, including collagenases [103,104,105].”
From The Roles of Vitamin C in Skin Health. (2017) · cites this paper as [104]
Cites
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Oxygen sensing by HIF hydroxylases
Schofield, C. J., & Ratcliffe, P. J. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1366 · Cited by 2,068 · see citing works
Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics
Semenza, G. L. (2010) · Oncogene · doi:10.1038/onc.2009.441 · Cited by 1,712 · see citing works
Lando, D., Peet, D. J., Gorman, J. J., Whelan, D. A., Whitelaw, M. L., & Bruick, R. K. (2002) · Genes & Development · doi:10.1101/gad.991402 · Cited by 1,550 · see citing works
HIF-1: upstream and downstream of cancer metabolism
Semenza, G. L. (2009) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2009.10.009 · Cited by 1,381 · see citing works
Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance
Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R. W., Washko, P. W., Dhariwal, K. R., Park, J. B., Lazarev, A., Graumlich, J. F., King, J., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.8.3704 · Cited by 1,325 · see citing works
Xiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · see citing works
Ascorbic acid: Chemistry, biology and the treatment of cancer
Du, J., Cullen, J. J., & Buettner, G. R. (2012) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2012.06.003 · Cited by 1,071 · see citing works
Hewitson, K. S., McNeill, L. A., Riordan, M. V., Tian, Y.-M., Bullock, A. N., Welford, R. W., Elkins, J. M., Oldham, N. J., Bhattacharya, S., Gleadle, J. M., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c200273200 · Cited by 719 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo
Gao, P., Zhang, H., Dinavahi, R., Li, F., Xiang, Y., Raman, V., Bhujwalla, Z. M., Felsher, D. W., Cheng, L., Pevsner, J., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.08.004 · Cited by 523 · see citing works
Koivunen, P., Hirsilä, M., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312254200 · Cited by 447 · see citing works
Distribution of ascorbic acid, metabolites and analogues in man and animals
Hornig, D. (1975) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1975.tb29271.x · Cited by 438 · see citing works
Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation
Wong, C. C.-L., Gilkes, D. M., Zhang, H., Chen, J., Wei, H., Chaturvedi, P., Fraley, S. I., Wong, C.-M., Khoo, U.-S., Ng, I. O.-L., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113483108 · Cited by 437 · see citing works
Cancer Development, Progression, and Therapy: An Epigenetic Overview
Sarkar, S., Horn, G., Moulton, K. L., Oza, A. U., Byler, S., Kokolus, S., & Longacre, M. M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141021087 · Cited by 392 · see citing works
pH control mechanisms of tumor survival and growth
Parks, S. K., Chiche, J., & Pouysségur, J. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22400 · Cited by 356 · see citing works
(2003) · PubMed · Cited by 350 · see citing works
Salnikow, K., Donald, S. P., Bruick, R. K., Zhitkovich, A., Phang, J. M., & Kasprzak, K. S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403057200 · Cited by 319 · see citing works
Masson, N., & Ratcliffe, P. J. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-3 · Cited by 296 · see citing works
Oxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
Ratcliffe, P. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251470 · Cited by 294 · see citing works
Structural studies on human 2-oxoglutarate dependent oxygenases
McDonough, M. A., Loenarz, C., Chowdhury, R., Clifton, I. J., & Schofield, C. J. (2010) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2010.08.006 · Cited by 280 · see citing works
Evans, R., Currie, L., & Campbell, A. (1982) · British Journal Of Nutrition · doi:10.1079/bjn19820059 · Cited by 226 · see citing works
Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway
Hirsilä, M., Koivunen, P., Xu, L., Seeley, T. W., Kivirikko, K. I., & Myllyharju, J. (2005) · The FASEB Journal · doi:10.1096/fj.04-3399fje · Cited by 220 · see citing works
Non-heme dioxygenases: cellular sensors and regulators jelly rolled into one?
Ozer, A., & Bruick, R. K. (2007) · Nature Chemical Biology · doi:10.1038/nchembio863 · Cited by 214 · see citing works
The role of ascorbate in the prolyl hydroxylase reaction
Myllylä, R., Kuutti-Savolainen, E.-R., & Kivirikko, K. I. (1978) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(78)91010-0 · Cited by 213 · see citing works
Vitamin C deficiency in cancer patients
Mayland, C. R., Bennett, M. I., & Allan, K. (2005) · Palliative Medicine · doi:10.1191/0269216305pm970oa · Cited by 199 · see citing works
FTO and Obesity: Mechanisms of Association
Zhao, X., Yang, Y., Sun, B.-F., Zhao, Y.-L., & Yang, Y. (2014) · Current Diabetes Reports · doi:10.1007/s11892-014-0486-0 · Cited by 187 · see citing works
Chen, H., Giri, N. C., Zhang, R., Yamane, K., Zhang, Y., Maroney, M. J., & Costa, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.058503 · Cited by 148 · see citing works
Kuiper, C., Molenaar, I. G. M., Dachs, G. U., Currie, M. J., Sykes, P. H., & Vissers, M. C. M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0263 · Cited by 135 · see citing works
Self-citationInterplay between Epigenetics and Genetics in Cancer
Choi, J. D., & Lee, J.-S. (2013) · Genomics & Informatics · doi:10.5808/gi.2013.11.4.164 · Cited by 131 · see citing works
The role of the hypoxia-inducible BH3-only proteins BNIP3 and BNIP3L in cancer
Mellor, H. R., & Harris, A. L. (2007) · Cancer and Metastasis Reviews · doi:10.1007/s10555-007-9080-0 · Cited by 129 · see citing works
Flashman, E., Davies, S. L., Yeoh, K. K., & Schofield, C. J. (2010) · Biochemical Journal · doi:10.1042/bj20091609 · Cited by 129 · see citing works
Modulation of hypoxia-inducible factor-1 alpha in cultured primary cells by intracellular ascorbate
Vissers, M. C. M., Gunningham, S. P., Morrison, M. J., Dachs, G. U., & Currie, M. J. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.11.023 · Cited by 125 · see citing works
Self-citationKuiper, C., Dachs, G. U., Currie, M. J., & Vissers, M. C. M. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.01.033 · Cited by 117 · see citing works
Self-citationAnthony, H. M., & Schorah, C. J. (1982) · British Journal of Cancer · doi:10.1038/bjc.1982.211 · Cited by 112 · see citing works
Prolyl 4-hydroxylase activity in relation to the oxidation state of enzyme-bound iron
de Jong, L., Albracht, S. P. J., & Kemp, A. (1982) · Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology · doi:10.1016/0167-4838(82)90162-5 · Cited by 111 · see citing works
CHA, J., Roomi, M. W., Ivanov, V. O., Kalinovsky, T., Niedzwiecki, A., & Rath, M. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1712 · Cited by 104 · see citing works
Salminen, A., Kaarniranta, K., Hiltunen, M. O., & Kauppinen, A. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.03.030 · Cited by 96 · see citing works
Sermeus, A., Cosse, J.-P., Crespin, M., Mainfroid, V., de Longueville, F., Ninane, N., Raes, M. J., Remacle, J., & Michiels, C. (2008) · Molecular Cancer · doi:10.1186/1476-4598-7-27 · Cited by 84 · see citing works
May, J. M., & Qu, Z.-C. (2005) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2004.10.023 · Cited by 79 · see citing works
Kuiper, C., Dachs, G. U., Munn, D., Currie, M. J., Robinson, B. A., Pearson, J. F., & Vissers, M. C. M. (2014) · Frontiers in Oncology · doi:10.3389/fonc.2014.00010 · Cited by 69 · see citing works
Self-citationEffect of ascorbic acid deficiency on the in vivo synthesis of carnitine
Nelson, P. J., Pruitt, R. E., Henderson, L. L., Jenness, R., & Henderson, L. M. (1981) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(81)90286-5 · Cited by 53 · see citing works
Multicompartmental secretion of ascorbate and its dual role in dopamineβ-hydroxylation
Diliberto, E. J., Daniels, A. J., & Viveros, O. H. (1991) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/54.6.1163s · Cited by 43 · see citing works
The role of ascorbate in the biosynthesis of neuroendocrine peptides
Eipper, B., & Mains, R. (1991) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/54.6.1153s · Cited by 41 · see citing works
Frycz, B. A., Murawa, D., Borejsza‐Wysocki, M., Marciniak, R., Murawa, P., Drews, M., Kolodziejczak, A. S., Tomela, K., & Jagodziński, P. P. (2014) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2013.12.011 · Cited by 30 · see citing works
Singleton, R. S., Trudgian, D. C., Fischer, R., Kessler, B. M., Ratcliffe, P. J., & Cockman, M. E. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.262808 · Cited by 24 · see citing works
The role of TET family proteins and 5-hydroxymethylcytosine in human tumors.
Wu, Y., & Ling, Z. (2014) · PubMed · doi:10.14670/hh-29.991 · Cited by 21 · see citing works
Kasprzak, K. S., Diwan, B. A., Kaczmarek, M. Z., Logsdon, D. L., Fivash, M. J., & Salnikow, K. (2011) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2011.08.015 · Cited by 21 · see citing works
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- Authors
- Vissers, M. C. M., Kuiper, C., & Dachs, G. U.
- Affiliations
- University of Otago (NZ)
- Corresponding author
- Kuiper, Caroline
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2014-08-01
- Volume
- 42
- Issue
- 4
- Pages
- 945-951
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- OpenAlex
- W2016242388
- Cited by
- 32
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 4 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 1
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- 2-oxoglutarate-dependent dioxygenase, hydroxylase, oxygen sensing, hypoxia-inducible factor, histone demethylation, DNA demethylation, epigenetic regulation, metabolic sensing, iron cofactor, vitamin C, tumor biology, cancer
- MeSH terms
- Animals, Humans, Ketoglutaric Acids, Neoplasms, Dioxygenases
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