Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases
- PMID: 22089927
- PMCID: PMC4197849
- DOI: 10.1101/sqb.2011.76.010975
Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases
Abstract
Hypoxia-inducible factor (HIF) deregulation contributes to the Warburg effect. HIF consists of an unstable α subunit and a stable β subunit. In the presence of oxygen, HIFα becomes prolyl hydroxylated by members of the EglN (also called PHD) family, leading to its proteasomal degradation. Under hypoxic conditions, EglN activity is diminished and HIF levels rise. EglN1 is the primary HIF prolyl hydroxylase with EglN2 and EglN3 playing compensatory roles under certain conditions. EglN2 and EglN3 also appear to play HIF-independent roles in regulating cell proliferation and apoptosis, respectively. The EglNs belong to a large family of 2-oxoglutarate-dependent dioxygenases that includes the TET DNA hydroxymethylases and JmjC-containing histone demethylases. Members of this superfamily can be inhibited by endogenous metabolites, including fumarate and succinate, which accumulate in tumors that have fumarate hydratase (FH) or succinate dehydrogenase (SDH) mutations, respectively, as well as by the 2-hydroxyglutarate detected in isocitrate dehydrogenase (IDH) mutant tumors. 2-Oxoglutarate-dependent dioxygenases therefore provide a link between altered metabolism and cancer.
Figures


Similar articles
-
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation.Nature. 2012 Feb 15;483(7390):484-8. doi: 10.1038/nature10898. Nature. 2012. PMID: 22343896 Free PMC article.
-
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. 2012 Jun 15;26(12):1326-38. doi: 10.1101/gad.191056.112. Epub 2012 Jun 7. Genes Dev. 2012. PMID: 22677546 Free PMC article.
-
2-Oxoglutarate-dependent dioxygenases in cancer.Nat Rev Cancer. 2020 Dec;20(12):710-726. doi: 10.1038/s41568-020-00303-3. Epub 2020 Oct 21. Nat Rev Cancer. 2020. PMID: 33087883 Review.
-
The multifaceted role of EGLN family prolyl hydroxylases in cancer: going beyond HIF regulation.Oncogene. 2022 Jul;41(29):3665-3679. doi: 10.1038/s41388-022-02378-8. Epub 2022 Jun 15. Oncogene. 2022. PMID: 35705735 Review.
-
Neuronal apoptosis by prolyl hydroxylation: implication in nervous system tumours and the Warburg conundrum.J Cell Mol Med. 2009 Oct;13(10):4104-12. doi: 10.1111/j.1582-4934.2009.00881.x. Epub 2009 Aug 19. J Cell Mol Med. 2009. PMID: 19691672 Free PMC article. Review.
Cited by
-
Hypoxic control of metastasis.Science. 2016 Apr 8;352(6282):175-80. doi: 10.1126/science.aaf4405. Epub 2016 Apr 7. Science. 2016. PMID: 27124451 Free PMC article. Review.
-
Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity.JCI Insight. 2019 Jul 25;4(14):e129398. doi: 10.1172/jci.insight.129398. eCollection 2019 Jul 25. JCI Insight. 2019. PMID: 31341109 Free PMC article.
-
The Chemical Biology of NO that Regulates Oncogenic Signaling and Metabolism: NOS2 and Its Role in Inflammatory Disease.Crit Rev Oncog. 2023;28(1):27-45. doi: 10.1615/CritRevOncog.2023047302. Crit Rev Oncog. 2023. PMID: 37824385 Free PMC article. Review.
-
STAT3 or USF2 contributes to HIF target gene specificity.PLoS One. 2013 Aug 21;8(8):e72358. doi: 10.1371/journal.pone.0072358. eCollection 2013. PLoS One. 2013. PMID: 23991099 Free PMC article.
-
von Hippel-Lindau Syndrome: Genetic Study of Case With a Rare Pathogenic Variant With Optic Nerve Hemangioblastoma, a Rare Phenotypic Expression.Front Oncol. 2020 Feb 14;10:139. doi: 10.3389/fonc.2020.00139. eCollection 2020. Front Oncol. 2020. PMID: 32117777 Free PMC article.
References
-
- Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279:38458–38465. - PubMed
-
- Arsham AM, Howell JJ, Simon MC. A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets. J Biol Chem. 2003;278:29655–29660. - PubMed
-
- Barrett A, Madsen B, Copier J, Lu PJ, Cooper L, Scibetta AG, Burchell J, Taylor-Papadimitriou J. PLU-1 nuclear protein, which is upregulated in breast cancer, shows restricted expression in normal human adult tissues: a new cancer/testis antigen? Int J Cancer. 2002;101:581–588. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous