PiB inhibits interaction between PIN1 and HIF-1α

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor that is induced by hypoxia. Specifically, the transcription of genes related to erythropoiesis, glycolysis, tissue invasion, metastasis and angiogenesis depends on the rate of HIF-1α binding to DNA at the hypoxia response elements of target genes. PIN1, the peptidyl-prolyl isomerase (PPIase), is an enzyme that changes the conformation of phosphoproteins. The conformational change induced by PIN1 alters the function and stability of the target proteins. PIN1 is overexpressed in many different types of malignancies, including breast, lung, cervical, brain and colorectal tumors. Thissuggests that PIN1 overexpression may function as a critical catalyst that amplifies multiple oncogenic signaling pathways during tumor development. In this study, wefocused on the interaction of PIN1with HIF-1α by using PiB, a selective inhibitor of PIN1.PiB binds to the active site of PIN1 and thereby inhibits its catalytic activity in a competitive manner by masking thesubstrate binding site of PIN1. Under hypoxic conditions, PiB inhibits interaction of PIN1 with HIF-1α. In addition, it destabilizes HIF-1α protein, consequently reducing expression of vescular endothelial growth factor (VEGF) which is a major target protein of HIF-1α and also tube formation in HUVEC. Moreover, in vivo angiogenesis was decreased by PiB. In conclusion, PiB blocks interaction between PIN1 and HIF-1α, which leads to downregulation of VEGF expression and suppression of angiogenesis.