Non-Canonical Mechanisms Regulating Hypoxia-Inducible Factor 1 Alpha in Cancer

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) orchestrates cellular adaptation to low oxygen and nutrient-deprived environment and drives progression to malignancy in human solid cancers. Its canonical regulation involves prolyl hydroxylases (PHDs), which in normoxia induce degradation, whereas in hypoxia allow stabilization of HIF-1 alpha. However, in certain circumstances, HIF-1 alpha regulation goes beyond the actual external oxygen levels and involves PHD-independent mechanisms. Here, we gather and discuss the evidence on the non-canonical HIF-1 alpha regulation, focusing in particular on the consequences of mitochondrial respiratory complexes damage on stabilization of this pleiotropic transcription factor.