The peptidyl prolyl isomerase, PIN1 induces angiogenesis through direct interaction with HIF-2α

Min-A Choi; Soma Saeidi; Hyeong-Jun Han; Su-Jung Kim; Nayoung Kwon; Do-Hee Kim; Sang-Hyun Min; Bu Young Choi; Young-Joon Surh

doi:10.1016/j.bbrc.2020.08.015

The peptidyl prolyl isomerase, PIN1 induces angiogenesis through direct interaction with HIF-2α

Biochem Biophys Res Commun. 2020 Dec 17;533(4):995-1003. doi: 10.1016/j.bbrc.2020.08.015. Epub 2020 Oct 2.

Authors

Min-A Choi¹, Soma Saeidi¹, Hyeong-Jun Han², Su-Jung Kim², Nayoung Kwon¹, Do-Hee Kim³, Sang-Hyun Min⁴, Bu Young Choi⁵, Young-Joon Surh⁶

Affiliations

¹ Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
² Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
³ Department of Chemistry, College of Convergence and Integrated Science, Kyonggi University, Suwon, Gyeonggi-do, 16227, South Korea.
⁴ New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu, 701-310, South Korea.
⁵ Department of Pharmaceutical Science and Engineering, School of Convergence Bioscience and Technology, Seowon University, Chungbuk, 28674, South Korea.
⁶ Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea. Electronic address: surh@snu.ac.kr.

PMID: 33012513
DOI: 10.1016/j.bbrc.2020.08.015

Abstract

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. PIN1 overexpression has been associated with activation of multiple oncogenic signaling pathways during tumor development. Hypoxia-inducible factor 2α (HIF-2α), a transcription factor activated in hypoxia, plays a role in erythropoiesis, glycolysis, tissue invasion, metastasis and angiogenesis. In this study, we found the direct interaction between HIF-2α and PIN1 in colorectal cancer HCT116 cells. Notably, serine 16 and lysine 63 residues of PIN1 were critical for its interaction with HIF-2α. When PIN1 protein was silenced by transient transfection of PIN1 short interfering RNA, the expression of HIF-2α was attenuated under a hypoxic condition. Moreover, genetic and pharmacologic inhibition of PIN1 abrogated the expression of vascular endothelial growth factor and angiogenesis. The cycloheximide chase experiment revealed the stabilization of HIF-2α by PIN1. Both WW and PPIase domains of PIN1 appear to be critical for its interaction with HIF-2α.

Keywords: Angiogenesis; HIF-2α; Hypoxia; PIN1; Peptidyl prolyl isomerase; VEGF.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors / chemistry
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Chick Embryo
Female
HCT116 Cells
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Male
Mice
NIH 3T3 Cells
NIMA-Interacting Peptidylprolyl Isomerase / chemistry
NIMA-Interacting Peptidylprolyl Isomerase / genetics
NIMA-Interacting Peptidylprolyl Isomerase / metabolism*
Neovascularization, Pathologic / etiology*
Neovascularization, Pathologic / genetics
Neovascularization, Pathologic / metabolism
Protein Interaction Domains and Motifs
Protein Stability
RNA Interference
RNA, Small Interfering / genetics
Tumor Hypoxia
Vascular Endothelial Growth Factor A / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
NIMA-Interacting Peptidylprolyl Isomerase
RNA, Small Interfering
VEGFA protein, human
Vascular Endothelial Growth Factor A
endothelial PAS domain-containing protein 1
PIN1 protein, human