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Prolyl Hydroxylase Domain Enzymes: Important Regulators of Cancer Metabolism

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Prolyl Hydroxylase Domain Enzymes: Important Regulators of Cancer Metabolism Hypoxia Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism Ming Yang1 Abstract: The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) Huizhong Su1 regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl Tomoyoshi Soga2 residues in its α subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIFα 3 under normal oxygen (O ) availability enables its association with the von Hippel-Lindau (VHL) Kamil R Kranc 2 Patrick J Pollard1 tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin- proteasome pathway. Due to the obligatory requirement of molecular O2 as a co-substrate, the 1Cancer Biology and Metabolism activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIF , which Group, Institute of Genetics and α Molecular Medicine, University of dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the Edinburgh, Edinburgh, UK; 2Institute transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, for Advanced Biosciences, Keio For personal use only. University, Mizukami, Tsuruoka, HIF plays important roles in multiple cellular processes and its overexpression has been detected Yamagata, Japan; 3MRC Centre for in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, Regenerative Medicine, University most notably by promoting anaerobic, whilst inhibiting O -dependent, metabolism of glucose. of Edinburgh, Edinburgh, UK 2 The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O2, such as by metabolic status, oxidative stress, and abnormal levels of endogenous metabolites (oncometabolites) that have been observed in some types of cancers. In this review, we aim to summarize current understandings of the function and regulation of PHDs in cancer with an emphasis on their roles in metabolism. Keywords: prolyl hydroxylase domain (PHD), hypoxia-inducible factor (HIF), metabolism, Hypoxia downloaded from https://www.dovepress.com/ by 54.191.40.80 on 03-Apr-2017 mouse models, hydroxylation, 2-oxoglutarate-dependent dioxygenases Introduction Low oxygen (O2) and nutrient availability are often encountered in solid tumors due to abnormal vasculature and rapid proliferation of cancer cells.1 Adaptation to these microenvironment changes involves alterations in the expression of genes that regu- late cellular energy production, biosynthesis, cell growth, and redox homeostasis. This response is, in part, mediated by the transcription factor hypoxia-inducible factor (HIF), a key regulator of the mammalian hypoxia response. The HIF signaling cascade encompasses diverse cellular pathways, some of which also intersect with tumorigenic processes.2,3 HIF is a heterodimeric transcription factor comprised of an O2-sensitive α subunit Correspondence: Patrick J Pollard and a constitutively expressed β subunit, both of which are basic helix-loop-helix Institute of Genetics and Molecular Per-ARNT-Sim domain proteins.4 The stability of HIF is primarily regulated by Medicine, Edinburgh Cancer Research UK Centre, University of Edinburgh, Western post-translational prolyl hydroxylation of HIFα, a reaction catalyzed by the HIF General Hospital, Crewe Road South, prolyl hydroxylase domain proteins (PHDs), a group of enzymes that act as O sen- Edinburgh EH4 2XR, UK 2 Email [email protected] sors in metazoans.5 PHD enzymes were first described roughly 10 years after the submit your manuscript | www.dovepress.com Hypoxia 2014:2 127–142 127 Dovepress © 2014 Yang et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/HP.S47968 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Yang et al Dovepress discovery of HIF.6–9 They are members of a large family and interstitial cells, whereas HIF3α is less well studied of non-heme iron-dependent dioxygenases that utilize and has multiple splice variants, some of which lack the ferrous iron (Fe(II)) as a co-factor to catalyze the four- transactivation domain present in HIF1α and HIF2α.5,11–13 electron reduction of molecular O2. They incorporate each Under normal O2 availability, HIFα is constantly expressed O2 atom, respectively, into the tricarboxylic acid (TCA) and hydroxylated by PHDs on two conserved prolyl residues cycle metabolite 2-oxoglutarate (2OG) and the substrate (Pro-405 and Pro-531 in HIF1α) present within an LXXLAP polypeptide, forming succinate, carbon dioxide, and, in the motif in its O2-dependent degradation domain. Trans-4-prolyl case of PHDs, trans-4-hydroxylated prolyl products.4 The hydroxylation confers a .1,000 fold increase in binding three main PHD isoforms, PHD1, PHD2, and PHD3 (also affinity to the protein pVHL (von Hippel-Lindau tumor sup- termed EGLN2, EGLN1, and EGLN3, respectively) have pressor), which is part of an E3-ubiquitin ligase complex overlapping but unique tissue expression patterns. PHD2 is that mediates ubiquitination and degradation of HIFα by the 14 present in most tissues, whereas PHD1 is mainly in testes 26S proteasome. Because O2 is an obligatory substrate for but also in brain, kidney, heart, and liver, and PHD3 showed PHDs, HIFαs escape PHD-dependent hydroxylation under highest expression in the heart.10 Both PHD2 and PHD3 are hypoxic conditions, translocate to the nucleus and dimerize strongly induced by hypoxia.7 The three isoforms share high with the β subunit (also termed ARNT), and through binding sequence homology in their C-terminal catalytic domains, to hypoxia-response elements in promoter regions of but not in their N-termini, the function of which remains to target genes, activate the transcription of its target genes be elucidated.8 (Figure 1). Another layer of regulation is conferred through There are three HIFα isoforms (HIF1α, HIF2α, and the hydroxylation of a specific asparaginyl residue (Asn-803 HIF3α). HIF1α is ubiquitously expressed; HIF2α expression in HIF1α) in the C-terminal activation domain of HIFα, is more cell-specific, such as in endothelial, parenchyma, a post-translational modification catalyzed by another R-2HG For personal use only. HIFα HIFα 2-Oxoglutarate 2-Oxoglutarate O2 O2 ROS Fumarate Fe2+ PHDs Fe2+ PHDs Hypoxia Succinate CO2 CO2 Succinate Succinate OH Hypoxia downloaded from https://www.dovepress.com/ by 54.191.40.80 on 03-Apr-2017 HIFα HIFα pVHL Nucleus p300/CBP OH HIFα HIFα HIFβ Ub Ub HRE Target genes Ub Activation of HIF transcriptional activity HIFα degradation Figure 1 PHDs are 2OG-dependent dioxygenases that regulate the stability of HIFα. In the presence of oxygen, PHDs post-translationally hydroxylate a prolyl residue in the NODDD and CODDD of HIFα subunits, which leads to its interaction with pVHL and ubiquitin-mediated degradation of HIFα by the 26S proteasome. Because PHDs have a low affinity for oxygen, they become inactive under hypoxic conditions, which allow HIFα to escape degradation, migrate to the nucleus, form a complex with the β subunit and transcriptional co-activators p300/CBP and regulate the transcription of its target genes by binding to hypoxia-responsive elements in their promoter regions. Fumarate and succinate structurally mimics 2OG (succinate is also a product of the reaction) and can competitively inhibit PHD activities when present at elevated concentrations, as observed in some cancer cells. R-2HG can enhance PHD activity and promote HIF degradation. In addition, ROS has also been suggested to modulate PHD activity. Abbreviations: 2OG, 2-oxoglutarate; CODDD, C-terminal oxygen-dependent degradation; HIF, hypoxia-inducible factor; HRE, hypoxia-responsive element; NODDD, N-terminal oxygen-dependent degradation; p300/CBP, p300/CREB-binding protein; OH, hydroxyl group; PHDs, prolyl hydroxylase domain proteins; R-2HG, (R)-2- hydroxyglutarate; ROS, reactive oxygen species; Ub, ubiquitin; pVHL, von Hippel–Lindau tumor suppressor. 128 submit your manuscript | www.dovepress.com Hypoxia 2014:2 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress PHDs as regulators of tumor metabolism 2OG-dependent dioxygenase termed factor-inhibiting HIF transporter 1, and facilitating glucose carbon efflux via lactate (FIH). β-hydroxylation of Asn-803 blocks the interaction by upregulating lactate dehydrogenase and monocarboxylate of HIFα with its transcriptional co-activators CBP (cAMP carrier MCT4.21–25 response element-binding protein)/p300, thereby inhibiting Pyruvate kinase (PK) catalyzes the final step in glyco- HIF activity. Unlike FIH, which has a relatively tight affin- lysis, converting phosphoenolpyruvate (PEP) to pyruvate. ity for O2 (Km value ∼90 µM), PHDs bind O2 loosely with The M2 isoform of pyruvate kinase (PKM2) is another gly- 4 26 Km values of each isoform in the range of 230–250 µM. colytic enzyme induced by HIF1α. PKM2 may be present
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