Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1
Abstract Understanding the mechanisms underlying chemoresistance is critical for improving cancer therapies. SIN1 plays a pivotal role in maintaining mTORC2 integrity and activation, which regulates key cellular processes. In this study, we demonstrate that elevated SIN1 expression in pancreatic duc...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07869-6 |
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| author | Yalei Wen Caishi Zhang Mingchao Liang Xiao Yang Hu Zeng Rui Wan Xiuqing Ma Lei Huang Mei Li Qiushi Zhang Liheng Li Shengying Qin Tongzheng Liu |
| author_facet | Yalei Wen Caishi Zhang Mingchao Liang Xiao Yang Hu Zeng Rui Wan Xiuqing Ma Lei Huang Mei Li Qiushi Zhang Liheng Li Shengying Qin Tongzheng Liu |
| author_sort | Yalei Wen |
| collection | DOAJ |
| description | Abstract Understanding the mechanisms underlying chemoresistance is critical for improving cancer therapies. SIN1 plays a pivotal role in maintaining mTORC2 integrity and activation, which regulates key cellular processes. In this study, we demonstrate that elevated SIN1 expression in pancreatic ductal adenocarcinoma (PDAC) correlates with poor patient survival outcomes. Conversely, SIN1 deletion reduces tumor growth and enhances PDAC sensitivity to chemotherapy. We identify USP33 as a bona fide deubiquitanase of SIN1, essential for its stabilization in PDAC. This stabilization promotes chemoresistance by activating the mTORC2-AKT pathway. Additionally, we show that CDK1 directly phosphorylates USP33, enhancing its deubiquitinase activity toward SIN1 and driving PDAC progression. Inhibition or genetic ablation of CDK1 significantly diminishes these malignant phenotypes. Furthermore, we observe a strong positive correlation between CDK1, USP33, and SIN1 expressions in PDAC tissues. Our results provide compelling preclinical evidence that targeting the CDK1–USP33 axis may offer a promising therapeutic strategy to destabilize SIN1 and overcome chemoresistance in PDAC and potentially other aggressive cancers. |
| format | Article |
| id | doaj-art-c31e26a79ee44841a0fa31137ea8d6b4 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-c31e26a79ee44841a0fa31137ea8d6b42025-08-20T04:02:44ZengNature Publishing GroupCell Death and Disease2041-48892025-07-0116111410.1038/s41419-025-07869-6Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1Yalei Wen0Caishi Zhang1Mingchao Liang2Xiao Yang3Hu Zeng4Rui Wan5Xiuqing Ma6Lei Huang7Mei Li8Qiushi Zhang9Liheng Li10Shengying Qin11Tongzheng Liu12Research Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityJianli Traditional Chinese Medicine HospitalThe Affiliated Shunde Hospital of Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityThe Sixth Affiliated Hospital of Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityState Key Laboratory of Bioactive Molecules and Druggability Assessment/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China/College of Pharmacy, Jinan UniversityResearch Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityDepartment of Interventional Radiology, The Affiliated Guangdong Second Provincial General Hospital of Jinan UniversityDepartment of Oncology, The First Affiliated Hospital of Jinan UniversityResearch Institute for Maternal and Child Health, The Affiliated Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan UniversityAbstract Understanding the mechanisms underlying chemoresistance is critical for improving cancer therapies. SIN1 plays a pivotal role in maintaining mTORC2 integrity and activation, which regulates key cellular processes. In this study, we demonstrate that elevated SIN1 expression in pancreatic ductal adenocarcinoma (PDAC) correlates with poor patient survival outcomes. Conversely, SIN1 deletion reduces tumor growth and enhances PDAC sensitivity to chemotherapy. We identify USP33 as a bona fide deubiquitanase of SIN1, essential for its stabilization in PDAC. This stabilization promotes chemoresistance by activating the mTORC2-AKT pathway. Additionally, we show that CDK1 directly phosphorylates USP33, enhancing its deubiquitinase activity toward SIN1 and driving PDAC progression. Inhibition or genetic ablation of CDK1 significantly diminishes these malignant phenotypes. Furthermore, we observe a strong positive correlation between CDK1, USP33, and SIN1 expressions in PDAC tissues. Our results provide compelling preclinical evidence that targeting the CDK1–USP33 axis may offer a promising therapeutic strategy to destabilize SIN1 and overcome chemoresistance in PDAC and potentially other aggressive cancers.https://doi.org/10.1038/s41419-025-07869-6 |
| spellingShingle | Yalei Wen Caishi Zhang Mingchao Liang Xiao Yang Hu Zeng Rui Wan Xiuqing Ma Lei Huang Mei Li Qiushi Zhang Liheng Li Shengying Qin Tongzheng Liu Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 Cell Death and Disease |
| title | Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 |
| title_full | Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 |
| title_fullStr | Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 |
| title_full_unstemmed | Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 |
| title_short | Phosphorylation of USP33 by CDK1 stabilizes the mTORC2 component SIN1 |
| title_sort | phosphorylation of usp33 by cdk1 stabilizes the mtorc2 component sin1 |
| url | https://doi.org/10.1038/s41419-025-07869-6 |
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