USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness
Abstract Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic event...
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07646-5 |
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| author | Zhenlei Zhang Xiujie Yu Liqi Wen Jia’nan Wang Zhufeng Li Yu Zhang Jiayu Cheng Ronglin Kan Wanting Zhang Yan Shen Shukai Yuan Li Zhao |
| author_facet | Zhenlei Zhang Xiujie Yu Liqi Wen Jia’nan Wang Zhufeng Li Yu Zhang Jiayu Cheng Ronglin Kan Wanting Zhang Yan Shen Shukai Yuan Li Zhao |
| author_sort | Zhenlei Zhang |
| collection | DOAJ |
| description | Abstract Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient-derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance. |
| format | Article |
| id | doaj-art-41b1ba45daeb49a6b6ce26299febd8f2 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-41b1ba45daeb49a6b6ce26299febd8f22025-08-20T02:27:06ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111810.1038/s41419-025-07646-5USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemnessZhenlei Zhang0Xiujie Yu1Liqi Wen2Jia’nan Wang3Zhufeng Li4Yu Zhang5Jiayu Cheng6Ronglin Kan7Wanting Zhang8Yan Shen9Shukai Yuan10Li Zhao11Department of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityTianjin Key Laboratory of Human Development and Reproductive Regulation, Department of Pathology, Tianjin Central Hospital of Gynaecology ObstericsDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of General Surgery, Tianjin Medical University General HospitalDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityTianjin Key Laboratory of Human Development and Reproductive Regulation, Department of Pathology, Tianjin Central Hospital of Gynaecology ObstericsDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityDepartment of Thyroid and Neck Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, Tianjin Medical UniversityAbstract Widespread intraperitoneal metastases and chemoresistance render ovarian cancer the leading cause of gynecological malignancy-related deaths, wherein TGF-β signaling plays the pivotal role by promoting cancer stem cells (CSCs) activity. The activation mechanism and key protumorigeneic events downstream of TGF-β signaling remain incompletely understood. Here, we identify hypoxic tumor microenvironment as an initiator of TGF-β signaling to promote HIF-2α positive CSC-mediated chemoresistance in high-grade serous ovarian cancer (HGSOC). Mechanistically, deubiquitinase USP9X, as a TGF-β downstream effector, stabilizes HIF-2ɑ in a hydroxylation- and ubiquitylation-dependent manner, thus promoting stemness reprogramming. Hypoxia and TGF-β signals converge on USP9X-HIF-2ɑ axis via multi-level regulations, which in turn facilitates Smad/HIF responses. Clinically, USP9X expression correlates with TGF-β signatures, CSCs characteristics, EMT behaviors, and chemotherapy responsiveness, along with HIF-2ɑ. Antagonizing USP9X efficiently represses tumor formation, metastasis, CSCs occurrence, while increasing chemosensitivity in orthotopic tumors, patient-derived xenograft (PDX), organoid, and chemoresistant cell models, in part via restricting TGF-β and hypoxia activities. This study deciphers the critical role of hypoxic niche in stimulating TGF-β signaling, and a downstream USP9X-HIF-2ɑ proteostatic regulatory axis in priming the HGSOC stemness, thereby provides novel targeting venues to counteract TGF-β signaling in CSCs and meliorate clinical chemoresistance.https://doi.org/10.1038/s41419-025-07646-5 |
| spellingShingle | Zhenlei Zhang Xiujie Yu Liqi Wen Jia’nan Wang Zhufeng Li Yu Zhang Jiayu Cheng Ronglin Kan Wanting Zhang Yan Shen Shukai Yuan Li Zhao USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness Cell Death and Disease |
| title | USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness |
| title_full | USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness |
| title_fullStr | USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness |
| title_full_unstemmed | USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness |
| title_short | USP9X integrates TGF-β and hypoxia signalings to promote ovarian cancer chemoresistance via HIF-2α-maintained stemness |
| title_sort | usp9x integrates tgf β and hypoxia signalings to promote ovarian cancer chemoresistance via hif 2α maintained stemness |
| url | https://doi.org/10.1038/s41419-025-07646-5 |
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