Fig. 1

Oxygen-dependent transcriptional regulation of HIFs. Under normoxic conditions, HIF-α protein is continually transcribed and rapidly degraded owing to the posttranslational hydroxylation of highly conserved proline residues by PHDs. Oxygen, Fe²⁺, and α-KG are substrates in this reaction. HIF-α, with hydroxyl group tags, subsequently interacts with the Von Hippel-Lindau protein (pVHL) E3 ubiquitin ligase complex for degradation via the ubiquitin–proteasome pathway. Under hypoxia, the activities of factor inhibiting HIFs (FIHs) and PHDs are suppressed, and thus HIF-α is stabilized and translocated into the nucleus to bind with HIF-β. Inhibition of PHDs and activation of p38 MAPK mediated by ROS are involved in HIF-α stabilization. With the help of transcriptional coactivators such as cyclic adenosine monophosphate response element-binding protein (CBP) and acetyltransferase (p300), the resultant heterodimeric HIF-α/β dimer binds to HREs and transcriptionally activates the targeted genes involved in malignant phenotypes and protumor mechanisms of PC. Abbreviations: Asn, asparagine; Pro, proline