Oxygen-independent stabilization of HIF-2α in breast cancer through direct interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1.

Autor: Guillen-Quispe YN; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea., Kim SJ; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea., Saeidi S; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea., Zhou T; Centre for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom; MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, EH4 2XU, United Kingdom., Zheng J; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea., Kim SH; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea., Fang X; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea., Chelakkot C; Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea., Rios-Castillo ME; School of Electronic Engineering, Faculty of Electronic and Electrical Engineering, National University of San Marcos, Lima, Peru., Shin YK; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Interdisciplinary Program in Bioinformatics, College of Natural Sciences, Seoul National University, Seoul, 41566, South Korea. Electronic address: ykeeshin@snu.ac.kr., Surh YJ; Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 08826, South Korea. Electronic address: surh@snu.ac.kr.
Jazyk: angličtina
Zdroj: Free radical biology & medicine [Free Radic Biol Med] 2023 Oct; Vol. 207, pp. 296-307. Date of Electronic Publication: 2023 Jul 19.
DOI: 10.1016/j.freeradbiomed.2023.07.020
Abstrakt: Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) isomerizes the nearby proline (Pro) residue when it detects phosphorylated serine (Ser) or threonine (Thr) of target proteins, altering their structure, stability, function, and interaction with other proteins. Hypoxia-inducible factor 2α (HIF-2α), a transcription factor that transactivates many oncogenic genes under hypoxic conditions, harbours the pSer/Thr-Pro motif. We found for the first time that Pin1 binds to HIF-2α physically in normoxic as well as hypoxic conditions in human breast cancer cells. The level of ubiquitinated HIF-2α was significantly raised by Pin1 knockdown, while expression of its mRNA transcript was unaffected. In agreement with this observation, the cycloheximide chase assay demonstrated that Pin1 prolonged the stability of HIF-2α. Serine 672, 696, and 790 of HIF-2α were found to undergo phosphorylation. Of these, the main amino acid involved in the Pin1 binding and HIF-2α stabilization was identified as serine 790, located in the nuclear export signal region of HIF-2α. The tissue array with human breast cancer specimens showed elevated expression of HIF-2α as well as Pin1 compared to adjacent normal tissues. Knockdown of Pin1 or HIF-2α diminished breast cancer cell migration and colony formation. In conclusion, Pin1 stabilizes HIF-2α through direct interaction, which contributes to the growth of breast cancer.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interest in relation to the submission and publication of this manuscript.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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