Fig. 1

Regulation of HIFs in hypoxic TME. In oxygenated conditions, HIF is hydroxylated on proline residues by PHDs, and then binds to pVHL, catalyzing its ubiquitination-dependent proteasomal degradation. In hypoxic conditions, PHDs inhibition allows HIF-α stabilization and translocation to the nucleus, where it heterodimerizes with HIF-1β. Then the HIF-1α/1β dimer binds to the transcriptional coactivator p300/CBP and HREs, activating transcription of various HIF target genes involved in angiogenesis, EMT, CSCs, metabolic reprogramming, tumor cell survival/proliferation, invasion/metastasis, and immune regulation