title: Prolyl hydroxylase domain enzymes: important regulators of cancer metabolism.
abstract: The hypoxia-inducible factor (HIF) prolyl hydroxylase domain enzymes (PHDs) regulate the stability of HIF protein by post-translational hydroxylation of two conserved prolyl residues in its α subunit in an oxygen-dependent manner.Trans-4-prolyl hydroxylation of HIFα under normal oxygen (O2) availability enables its association with the von Hippel-Lindau (VHL) tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFα via the ubiquitin-proteasome pathway. Due to the obligatory requirement of molecular O2as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIFα, which dimerizes with HIFβ and, together with transcriptional co-activators CBP/p300, activates the transcription of its target genes. As a key molecular regulator of adaptive response to hypoxia, HIF plays important roles in multiple cellular processes and its overexpression has been detected in various cancers. The HIF1α isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O2-dependent, metabolism of glucose. 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.
authors: Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: Ming
authors: M
authors: Yang
authors: Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: Huizhong
authors: H
authors: Su
authors: Institute for Advanced Biosciences, Keio University, Mizukami, Tsuruoka, Yamagata, Japan.
authors: Tomoyoshi
authors: T
authors: Soga
authors: MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors: Kamil R
authors: KR
authors: Kranc
authors: Cancer Biology and Metabolism Group, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: Patrick J
authors: PJ
authors: Pollard
keywords: 2-oxoglutarate-dependent dioxygenases; hydroxylation; hypoxia-inducible factor (HIF); metabolism; mouse models; prolyl hydroxylase domain (PHD)