<br>通过与肽基-脯氨酰顺反异构酶 NIMA 相互作用的直接相互作用，HIF-2α 在乳腺癌中不依赖氧地稳定 1,Free Radical Biology and Medicine

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通过与肽基-脯氨酰顺反异构酶 NIMA 相互作用的直接相互作用，HIF-2α 在乳腺癌中不依赖氧地稳定 1
Free Radical Biology and Medicine ( IF 7.1 ) Pub Date : 2023-07-19 , DOI: 10.1016/j.freeradbiomed.2023.07.020
Yanymee N Guillen-Quispe ₁ , Su-Jung Kim ₂ , Soma Saeidi ₁ , Tianchi Zhou ₃ , Jie Zheng ₂ , Seong Hoon Kim ₂ , Xizhu Fang ₂ , Chaithanya Chelakkot ₄ , Milton E Rios-Castillo ₅ , Young Kee Shin ₆ , Young-Joon Surh ₇

Affiliation

Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
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.
Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
School of Electronic Engineering, Faculty of Electronic and Electrical Engineering, National University of San Marcos, Lima, Peru.
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.
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.

肽基-脯氨酰顺反异构酶 NIMA 相互作用 1 （Pin1）在检测靶蛋白的磷酸化丝氨酸（Ser）或苏氨酸（Thr）时，会异构化附近的脯氨酸（Pro）残基，从而改变其结构、稳定性、功能以及与其他蛋白的相互作用。缺氧诱导因子 2α （HIF-2α）是一种在缺氧条件下反式激活许多致癌基因的转录因子，具有 pSer/Thr-Pro 基序。我们首次发现 Pin1 在人乳腺癌细胞的常氧和缺氧条件下与 HIF-2α 物理结合。Pin1 敲低显著提高了泛素化 HIF-2α 的水平，而其 mRNA 转录本的表达不受影响。与这一观察结果一致，放线菌酮追踪测定表明 Pin1 延长了 HIF-2α 的稳定性。发现 HIF-2α 的丝氨酸 672、696 和 790 发生磷酸化。其中，参与 Pin1 结合和 HIF-2α 稳定化的主要氨基酸被鉴定为丝氨酸 790，位于 HIF-2α 的核输出信号区域。与邻近正常组织相比，人乳腺癌标本的组织阵列显示 HIF-2α 和 Pin1 的表达升高。敲低 Pin1 或 HIF-2α 减少了乳腺癌细胞迁移和集落形成。总之，Pin1 通过直接相互作用稳定 HIF-2α，这有助于乳腺癌的生长。

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

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.

更新日期：2023-07-19

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