Peptidyl Prolyl Isomerase PIN1 Directly Binds to and Stabilizes Hypoxia-Inducible Factor-1α

Abstract

Peptidyl prolyl isomerase (PIN1) regulates the functional activity of a subset of phosphoproteins through binding to phosphorylated Ser/Thr-Pro motifs and subsequently isomerization of the phosphorylated bonds. Interestingly, PIN1 is overexpressed in many types of malignancies including breast, prostate, lung and colon cancers. However, its oncogenic functions have not been fully elucidated. Here, we report that PIN1 directly interacts with hypoxia-inducible factor (HIF)-1α in human colon cancer (HCT116) cells. PIN1 binding to HIF-1α occurred in a phosphorylation-dependent manner. We also found that PIN1 interacted with HIF-1α at both exogenous and endogenous levels. Notably, PIN1 binding stabilized the HIF-1α protein, given that their levels were significantly increased under hypoxic conditions. The stabilization of HIF-1α resulted in increased transcriptional activity, consequently upregulating expression of vascular endothelial growth factor, a major contributor to angiogenesis. Silencing of PIN1 or pharmacologic inhibition of its activity abrogated the angiogenesis. By utilizing a bioluminescence imaging technique, we were able to demonstrate that PIN1 inhibition dramatically reduced the tumor volume in a subcutaneous mouse xenograft model and angiogenesis as well as hypoxia-induced transcriptional activity of HIF-1α. These results suggest that PIN1 interacting with HIF-1α is a potential cancer chemopreventive and therapeutic target.

Prolyl Isomerase Pin1 in Human Cancer: Function, Mechanism, and Significance

“…Hypoxia-inducible factor 1α (HIF-1α) is responsible for promoting the expression of many genes involved in angiogenesis (Rosmorduc and Housset, 2010). Pin1 directly interacts with HIF-1α at both exogenous and endogenous levels to stabilize the HIF-1α protein in human colon cancer cells and upregulating expression of VEGF, a major contributor to angiogenesis (Han et al, 2016). Moreover, Pin1 cooperates with KLHL20 to induce the ubiquitindependent degradation of PML, an inhibitor of HIF-1α-induced angiogenesis, resulting in the activation of angiogenesis in many cancers (Yuan et al, 2011).…”

Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

“…Other transcription factors regulated by Pin1 at the level of protein stability include RelA (Ryo et al, 2003), β-catenin (Ryo et al, 2001), IRF3 (Saitoh et al, 2006), Naong (Moretto-Zita et al, 2010), Oct4 (Nishi et al, 2011), MEF2C (Magli et al, 2010), SP1 (Yang et al, 2014), Osterix (Lee et al, 2015), ATF1 (Huang et al, 2016), TR3 (Chen et al, 2012), FoxM1 (Kruiswijk et al, 2016;Wang et al, 2016), Smad3 (Nakano et al, 2009), RAR (Gianni et al, 2009), FoxO3 (Shimizu et al, 2016), PPARγ (Fujimoto et al, 2010;, and HIF-1a (Han H. J. et al, 2016) (Table 1). The detailed mechanisms for how Pin1 regulates their stability might be different for each factor, it appears that changing the accessibility of E3 ligases to the Pin1 substrates due to Pin1-medaited protein conformational change via isomerization might represent a general mechanism for the regulation of protein stability by Pin1.…”

Selective HIF-1 Regulation under Nonhypoxic Conditions by the p42/p44 MAP Kinase Inhibitor PD184161

“…HIF-1a phosphorylation permits binding by a proline isomerase, Pin1, which is indispensable for full HIF-1 transcriptional activity. (Jalouli et al, 2014;Han et al, 2016). Under normal O 2 , HIF-1 is also activated by different cellular stimuli, a condition we described as nonhypoxic HIF-1 activation.…”