Prolyl Hydroxylase Domain Enzymes: Important Regulators Of Cancer Metabolism

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 a subunit in an oxygen-dependent manner. Trans-4-prolyl hydroxylation of HIF alpha under normal oxygen (O-2) availability enables its association with the von Hippel-Lindau (VHL) tumor suppressor pVHL E3 ligase complex, leading to the degradation of HIFa via the ubiquitinproteasome pathway. Due to the obligatory requirement of molecular O-2 as a co-substrate, the activity of PHDs is inhibited under hypoxic conditions, resulting in stabilized HIF alpha, which dimerizes with HIF beta 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 HIF1 alpha isoform in particular has a strong impact on cellular metabolism, most notably by promoting anaerobic, whilst inhibiting O-2-dependent, metabolism of glucose. The PHD enzymes also seem to have HIF-independent functions and are subject to regulation by factors other than O-2, 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.