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 O2 as 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.

In Vitro Innovation of Tendon Tissue Engineering Strategies

“…In cellular or tissue normoxic, or physiological normoxia, environments, HIF1a is constantly expressed, but its conserved proline residues are hydroxylated by Prolyl hydroxylase domain enzymes (PHDs). This oxygen-dependent hydroxylation creates a binding site for the von Hippel-Lindau (VHL) protein, which is a component of the E3 ubiquitin ligase complex that leads the HIF1α subunit to proteasomal destruction [222]. When lower than normoxic oxygen concentrations occur, the HIF-1α protein is stabilized and accumulates inside the nucleus [223], where it can induce the transcription of many genes with adaptive functions [224].…”

Genetically Encoded Tools for Research of Cell Signaling and Metabolism under Brain Hypoxia

“…Moreover, it is useful to keep in mind that PHD isoforms demonstrate different tissue distribution and selectivity. Additional information about these enzymes can be found in the following reviews [38,132].…”

Dysregulation of 2-oxoglutarate-dependent dioxygenases by hyperglycaemia: does this link diabetes and vascular disease?

“…As stated above, molecular oxygen is an obligate substrate for all 2-OGDDs, of which the best characterised are the related hypoxia-inducible factor-1 prolyl hydrox ylases (HIF-PHD1-3). Under normoxic conditions, PHDs hydroxylate HIF1α, leading to its association with von Hippel-Lindau and subsequent degradation [62]. The inhibition of PHDs by relative hypoxia, due to their requirement for molecular oxygen, leads to HIF stabilisation and HIF-dependent activation of transcription [62].…”

“…Under normoxic conditions, PHDs hydroxylate HIF1α, leading to its association with von Hippel-Lindau and subsequent degradation [62]. The inhibition of PHDs by relative hypoxia, due to their requirement for molecular oxygen, leads to HIF stabilisation and HIF-dependent activation of transcription [62]. Studies performed to determine the K M values for O 2 of these enzymes suggest that their activities may be modulated by fluctuations in [O 2 ] over physiological ranges, at least in some tissues, further substantiating their roles as bona fide O 2 sensors [63].…”