USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer
Abstract Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to iden...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07424-3 |
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| author | Zhongdong Xie Hanbin Lin Yuecheng Wu Yanan Yu Xintong Liu Yating Zheng Xiaojie Wang Jiashu Wu Meifang Xu Yuting Han Qiongying Zhang Yu Deng Lin Lin Yan Linzhu Li Qingyun Xinjian Lin Ying Huang Pan Chi |
| author_facet | Zhongdong Xie Hanbin Lin Yuecheng Wu Yanan Yu Xintong Liu Yating Zheng Xiaojie Wang Jiashu Wu Meifang Xu Yuting Han Qiongying Zhang Yu Deng Lin Lin Yan Linzhu Li Qingyun Xinjian Lin Ying Huang Pan Chi |
| author_sort | Zhongdong Xie |
| collection | DOAJ |
| description | Abstract Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC. |
| format | Article |
| id | doaj-art-31b63ca207ff490b9782c985eef2ce8e |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-31b63ca207ff490b9782c985eef2ce8e2025-02-09T12:56:52ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111510.1038/s41419-025-07424-3USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancerZhongdong Xie0Hanbin Lin1Yuecheng Wu2Yanan Yu3Xintong Liu4Yating Zheng5Xiaojie Wang6Jiashu Wu7Meifang Xu8Yuting Han9Qiongying Zhang10Yu Deng11Lin Lin12Yan Linzhu13Li Qingyun14Xinjian Lin15Ying Huang16Pan Chi17Department of Colorectal Surgery, Union Hospital, Fujian Medical UniversityCentral Laboratory, Affiliated Hospital of Putian UniversityKey Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationGuilin Medical UniversityCentral Laboratory, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityDepartment of Science and Technology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Pathology, Union Hospital, Fujian Medical UniversityKey Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationDepartment of Pathology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityDepartment of Pathology, Union Hospital, Fujian Medical UniversityDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityKey Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of EducationDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityDepartment of Colorectal Surgery, Union Hospital, Fujian Medical UniversityAbstract Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.https://doi.org/10.1038/s41419-025-07424-3 |
| spellingShingle | Zhongdong Xie Hanbin Lin Yuecheng Wu Yanan Yu Xintong Liu Yating Zheng Xiaojie Wang Jiashu Wu Meifang Xu Yuting Han Qiongying Zhang Yu Deng Lin Lin Yan Linzhu Li Qingyun Xinjian Lin Ying Huang Pan Chi USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer Cell Death and Disease |
| title | USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer |
| title_full | USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer |
| title_fullStr | USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer |
| title_full_unstemmed | USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer |
| title_short | USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer |
| title_sort | usp4 mediated cenpf deubiquitylation regulated tumor metastasis in colorectal cancer |
| url | https://doi.org/10.1038/s41419-025-07424-3 |
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