Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis
Abstract Stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which plays a pivotal role in regulating cellular responses to insufficient oxygen, is implicated in cancer progression, particularly epithelial-mesenchymal transition and metastatic dissemination. Despite its crucial role in tumori...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-025-02314-8 |
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| author | Hye-Kyung Park Sung Hu So Yeon Kim Sora Yoon Nam Gu Yoon Ji Hye Lee Wonyoung Choi Sun-Young Kong Jong Heon Kim Dougu Nam Byoung Heon Kang |
| author_facet | Hye-Kyung Park Sung Hu So Yeon Kim Sora Yoon Nam Gu Yoon Ji Hye Lee Wonyoung Choi Sun-Young Kong Jong Heon Kim Dougu Nam Byoung Heon Kang |
| author_sort | Hye-Kyung Park |
| collection | DOAJ |
| description | Abstract Stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which plays a pivotal role in regulating cellular responses to insufficient oxygen, is implicated in cancer progression, particularly epithelial-mesenchymal transition and metastatic dissemination. Despite its crucial role in tumorigenesis, the precise mechanisms governing HIF1α stabilization under varying tumor microenvironmental conditions are not fully understood. In this study, we show that stabilization of HIF1α in metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species (ROS) rather than by reduced oxygen levels. Activated HIF1α suppresses the expression of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a. Reduced expression of CypD leads to mPTP closure, resulting in elevated mitochondrial calcium accumulation and enhanced oxidative phosphorylation, which in turn increases mitochondrial ROS levels. The ROS then inhibits a prolyl hydroxylase, establishing a pseudohypoxic state that stabilizes HIF1α even in the presence of oxygen. This HIF1-reinforced and mitochondria-driven pseudohypoxic induction is essential for maintaining HIF1 signaling under conditions of mild hypoxia or transient increases in oxygen levels during melanoma metastasis. Overexpression of CypD reversed the pseudohypoxic state and potently inhibited melanoma metastasis. Thus, mitochondria-driven pseudohypoxic induction is critical for sustaining HIF1 signaling in metastasizing cancer cells and can be exploited to develop anti-metastatic therapies. |
| format | Article |
| id | doaj-art-2f62d39dba1a4ed8be47315e732f41d4 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-2f62d39dba1a4ed8be47315e732f41d42025-08-20T03:41:57ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-07-0110111510.1038/s41392-025-02314-8Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasisHye-Kyung Park0Sung Hu1So Yeon Kim2Sora Yoon3Nam Gu Yoon4Ji Hye Lee5Wonyoung Choi6Sun-Young Kong7Jong Heon Kim8Dougu Nam9Byoung Heon Kang10Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Genetics, University of PennsylvaniaDepartment of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and PolicyDepartment of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and PolicyDepartment of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and PolicyDepartment of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST)Abstract Stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which plays a pivotal role in regulating cellular responses to insufficient oxygen, is implicated in cancer progression, particularly epithelial-mesenchymal transition and metastatic dissemination. Despite its crucial role in tumorigenesis, the precise mechanisms governing HIF1α stabilization under varying tumor microenvironmental conditions are not fully understood. In this study, we show that stabilization of HIF1α in metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species (ROS) rather than by reduced oxygen levels. Activated HIF1α suppresses the expression of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a. Reduced expression of CypD leads to mPTP closure, resulting in elevated mitochondrial calcium accumulation and enhanced oxidative phosphorylation, which in turn increases mitochondrial ROS levels. The ROS then inhibits a prolyl hydroxylase, establishing a pseudohypoxic state that stabilizes HIF1α even in the presence of oxygen. This HIF1-reinforced and mitochondria-driven pseudohypoxic induction is essential for maintaining HIF1 signaling under conditions of mild hypoxia or transient increases in oxygen levels during melanoma metastasis. Overexpression of CypD reversed the pseudohypoxic state and potently inhibited melanoma metastasis. Thus, mitochondria-driven pseudohypoxic induction is critical for sustaining HIF1 signaling in metastasizing cancer cells and can be exploited to develop anti-metastatic therapies.https://doi.org/10.1038/s41392-025-02314-8 |
| spellingShingle | Hye-Kyung Park Sung Hu So Yeon Kim Sora Yoon Nam Gu Yoon Ji Hye Lee Wonyoung Choi Sun-Young Kong Jong Heon Kim Dougu Nam Byoung Heon Kang Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis Signal Transduction and Targeted Therapy |
| title | Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis |
| title_full | Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis |
| title_fullStr | Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis |
| title_full_unstemmed | Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis |
| title_short | Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis |
| title_sort | pseudohypoxic stabilization of hif1α via cyclophilin d suppression promotes melanoma metastasis |
| url | https://doi.org/10.1038/s41392-025-02314-8 |
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