Abstract 599: Regulation of hypoxia-inducible factor stability by peptidyl prolyl isomerase Pin1

Abstract

Abstract Pin1 is an isomerase that binds to phosphorylated Ser/Thr-Pro motifs and regulates a subset of phosphoproteins through isomerization of the phosphorylated bonds. Pin1 has been reported to play an important role in differentiation, cell proliferation and immune responses. Interestingly, Pin1 is overexpressed in many types of cancer tissues including breast, prostate, lung and colon. However, molecular mechanism underlying its oncogenic functions has not been fully elucidated. Here, we report that Pin1 directly or indirectly interacts with hypoxia-inducible factor (HIF) -1α and -2α in HCT116 cells. Pin1 can bind both HIF-1α and -2α in vitro. We also found that Pin1 interacted more strongly with HIF-2α than with HIF-1α at the endogenous level. Pin1 binding may cause stabilization of HIF-1α and HIF-2α protein, given that their levels were significantly increased under hypoxic condition. Pin1 knockdown decreased the expression of HIF-1α and HIF-2α proteins and vascular endothelial growth factor (VEGF) mRNA under hypoxic conditions. On the other hand, overexpression of Pin1 resulted in an increase in HIF-1α protein levels in hypoxic cells, and enhanced hypoxia-induced VEGF transcriptional activation. These results suggest that Pin1 interplays with HIF-1α and -2α, and is a potential chemopreventive and therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 599. doi:1538-7445.AM2012-599