Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011:76:335-45.
doi: 10.1101/sqb.2011.76.010975. Epub 2011 Nov 16.

Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases

Affiliations
Review

Cancer and altered metabolism: potential importance of hypoxia-inducible factor and 2-oxoglutarate-dependent dioxygenases

W G Kaelin Jr. Cold Spring Harb Symp Quant Biol. 2011.

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.

PubMed Disclaimer

Figures

Fig 1
Fig 1. 2-Oxoglutarate-dependent Dioxygenase Reaction
2-Oxoglutarate-dependent enzymes require 2-oxoglutarate (also called alpha ketoglutarate), oxygen, and reduced iron to hydroxylate their substrates. 2-oxoglutarate is decarboxylated to succinate during the reaction. In the cases of histone demethylases a methyl group is hydroxylated and the resulting hydroxymethyl group is spontaneously given off as formaldehyde. These enzymes are variably susceptible to inhibition by Krebs Cycle intermediates such a succinate and fumarate, to 2-hydroxyglutarate, and to reactive oxygen species.
Fig 2
Fig 2. Central Role of HIF in Warburg Metabolism
Many oncogenic mutations lead to increased HIF accumulation, which promotes the Warburg Effect. Increase Myc expression and loss of p53 function can also contribute to such metabolic changes.

Similar articles

Cited by

References

    1. Agger K, Cloos PA, Rudkjaer L, Williams K, Andersen G, Christensen J, Helin K. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23:1171–1176. - PMC - PubMed
    1. 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
    1. 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
    1. Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenfuhr M, Maertens G, Banck M, Zhou MM, Walsh MJ, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23:1177–1182. - PMC - PubMed
    1. 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

Substances

LinkOut - more resources