The non-canonical functions of HIF prolyl hydroxylases and their dual roles in cancer

The hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are dioxygenases using oxygen and 2-oxoglutarate as co-substrates. Under normoxia, PHDs hydroxylate the conserved prolyl residues of HIF alpha, leading to HIF alpha degradation. In hypoxia PHDs are inactivated, which results in HIF alpha accumulation. The accumulated HIF alpha enters nucleus and initiates gene transcription. Many studies have shown that PHDs have substrates other than HIF alpha, implying that they have HIF-independent non-canonical functions. Besides modulating protein stability, the PHDs-mediated prolyl hydroxylation affects protein-protein interaction and protein activity for alternative substrates. Increasing evidence indicates that PHDs also have hydroxylase-independent functions. They influence protein stability, enzyme activity, and protein-protein interaction in a hydroxylase-independent manner. These findings highlight the functional diversity and complexity of PHDs. Due to having inhibitory activity on HIF alpha, PHDs are proposed to act as tumor suppressors. However, research shows that PHDs exert either tumorpromoting or tumor-suppressing features. Here, we try to summarize the current understanding of PHDs hydroxylase-dependent and -independent functions and their roles in cancer.

Automated summary

The hypoxia-inducible factor prolyl hydroxylases (PHDs) are enzymes that regulate the response to oxygen levels by hydroxylating prolyl residues of HIF alpha. Studies show they also have additional functions in protein stability, enzyme activity, and protein-protein interactions.