title: 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.
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hyeong-Jun
authors.initials: HJ
authors.lastname: Han
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kwon
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Min-A
authors.initials: MA
authors.lastname: Choi
authors.affiliation: Department of Nuclear Medicine, Seoul National University, Seoul, 136-742, South Korea.|Biomedical Sciences, Seoul National University, Seoul, 136-742, South Korea.|Cancer Research Institute, Seoul National University, Seoul, 136-742, South Korea.
authors.forename: Kyung Oh
authors.initials: KO
authors.lastname: Jung
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Juan-Yu
authors.initials: JY
authors.lastname: Piao
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Hoang Kieu Chi
authors.initials: HK
authors.lastname: Ngo
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Do-Hee
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Seoul National University, Seoul, 136-742, South Korea.|Biomedical Sciences, Seoul National University, Seoul, 136-742, South Korea.|Cancer Research Institute, Seoul National University, Seoul, 136-742, South Korea.
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
authors.affiliation: College of Medicine, Inha University, Incheon, South Korea.
authors.forename: Young-Nam
authors.initials: YN
authors.lastname: Cha
authors.affiliation: Department of Nuclear Medicine, Seoul National University, Seoul, 136-742, South Korea.|Cancer Research Institute, Seoul National University, Seoul, 136-742, South Korea.|Cancer Imaging Center, Seoul National University Hospital, Seoul, 136-742, South Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Youn
authors.affiliation: Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Cheongju, 361-742, South Korea.
authors.forename: Bu Young
authors.initials: BY
authors.lastname: Choi
authors.affiliation: New Drug Development Center DGMIF, Daegu, 701-310, South Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Min
authors.affiliation: Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, South Korea.|Cancer Research Institute, Seoul National University, Seoul, 136-742, South Korea.|Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 151-742, South Korea.
authors.forename: Young-Joon
authors.initials: YJ
authors.lastname: Surh
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation; D055550:Protein Stability; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse