F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression
Abstract D-type cyclins (hereafter, cyclin D) are central regulators orchestrating G1/S cell cycle transition. Accordingly, aberrant expression of cyclin D is strongly correlated with proliferation-related diseases such as cancer. However, the mechanisms regulating cyclin D turnover are incompletely...
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59407-9 |
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| author | Feng Li Hongqiang Yu Yujun Zhang Yuanhang Ma Xinlei Chen Jie Zhang Liangbo Sun Rui Guo Ying Wu Ping Zheng Xiaojun Wang Ping Bie Fengtian He Leida Zhang Chuanming Xie Haojun Xiong |
| author_facet | Feng Li Hongqiang Yu Yujun Zhang Yuanhang Ma Xinlei Chen Jie Zhang Liangbo Sun Rui Guo Ying Wu Ping Zheng Xiaojun Wang Ping Bie Fengtian He Leida Zhang Chuanming Xie Haojun Xiong |
| author_sort | Feng Li |
| collection | DOAJ |
| description | Abstract D-type cyclins (hereafter, cyclin D) are central regulators orchestrating G1/S cell cycle transition. Accordingly, aberrant expression of cyclin D is strongly correlated with proliferation-related diseases such as cancer. However, the mechanisms regulating cyclin D turnover are incompletely elucidated. Here we identify FBXO32, namely atrogin-1, as the E3 ubiquitin ligase that targets all three cyclin D for ubiquitination and stabilization. Specifically, FBXO32 catalyzes the lysine (Lys/K)27-linked polyubiquitination of cyclin D1 at the K58 site and subsequent stabilization. Moreover, GSK-3β inactivation-mediated dephosphorylation of cyclin D1 facilitates its interaction with FBXO32 and subsequent ubiquitination. Furthermore, FBXO32 exhibits tumor-promoting effect in mouse models and increased FBXO32 is associated with poor prognosis of cancer patients. Additionally, disrupting the FBXO32-cyclin D axis enhances the tumor-killing effect of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib. Collectively, these findings reveal that FBXO32 enhances the protein stability of cyclin D via K27-linked ubiquitination, and contributes to cancer progression and the limited response of cancer cells to CDK4/6 inhibitors. |
| format | Article |
| id | doaj-art-3080bc4af35d4e958ec0dc2191c034d1 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
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| series | Nature Communications |
| spelling | doaj-art-3080bc4af35d4e958ec0dc2191c034d12025-08-20T01:47:32ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-59407-9F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progressionFeng Li0Hongqiang Yu1Yujun Zhang2Yuanhang Ma3Xinlei Chen4Jie Zhang5Liangbo Sun6Rui Guo7Ying Wu8Ping Zheng9Xiaojun Wang10Ping Bie11Fengtian He12Leida Zhang13Chuanming Xie14Haojun Xiong15Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityDepartment of General Surgery, Xinqiao Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityDepartment of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityDepartment of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical UniversityDepartment of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityKey Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Army Medical UniversityAbstract D-type cyclins (hereafter, cyclin D) are central regulators orchestrating G1/S cell cycle transition. Accordingly, aberrant expression of cyclin D is strongly correlated with proliferation-related diseases such as cancer. However, the mechanisms regulating cyclin D turnover are incompletely elucidated. Here we identify FBXO32, namely atrogin-1, as the E3 ubiquitin ligase that targets all three cyclin D for ubiquitination and stabilization. Specifically, FBXO32 catalyzes the lysine (Lys/K)27-linked polyubiquitination of cyclin D1 at the K58 site and subsequent stabilization. Moreover, GSK-3β inactivation-mediated dephosphorylation of cyclin D1 facilitates its interaction with FBXO32 and subsequent ubiquitination. Furthermore, FBXO32 exhibits tumor-promoting effect in mouse models and increased FBXO32 is associated with poor prognosis of cancer patients. Additionally, disrupting the FBXO32-cyclin D axis enhances the tumor-killing effect of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib. Collectively, these findings reveal that FBXO32 enhances the protein stability of cyclin D via K27-linked ubiquitination, and contributes to cancer progression and the limited response of cancer cells to CDK4/6 inhibitors.https://doi.org/10.1038/s41467-025-59407-9 |
| spellingShingle | Feng Li Hongqiang Yu Yujun Zhang Yuanhang Ma Xinlei Chen Jie Zhang Liangbo Sun Rui Guo Ying Wu Ping Zheng Xiaojun Wang Ping Bie Fengtian He Leida Zhang Chuanming Xie Haojun Xiong F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression Nature Communications |
| title | F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression |
| title_full | F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression |
| title_fullStr | F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression |
| title_full_unstemmed | F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression |
| title_short | F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression |
| title_sort | f box protein fbxo32 ubiquitinates and stabilizes d type cyclins to drive cancer progression |
| url | https://doi.org/10.1038/s41467-025-59407-9 |
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