NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination
Abstract The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what...
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Nature Publishing Group
2024-11-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-024-02243-5 |
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| author | Zhen Chen Weilong Wang Jinghan Hou Can Gao Meili Song Zijun Zhao Ruirui Guan Jingsheng Chen Huicheng Wu Siti Razila Abdul Razak Tao Han Junbo Zhang Lidong Wang Nor Hazwani Ahmad Xiumin Li |
| author_facet | Zhen Chen Weilong Wang Jinghan Hou Can Gao Meili Song Zijun Zhao Ruirui Guan Jingsheng Chen Huicheng Wu Siti Razila Abdul Razak Tao Han Junbo Zhang Lidong Wang Nor Hazwani Ahmad Xiumin Li |
| author_sort | Zhen Chen |
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| description | Abstract The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC. |
| format | Article |
| id | doaj-art-ea75cff8dfa6477db7d477f12b7916ee |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-ea75cff8dfa6477db7d477f12b7916ee2025-08-20T02:33:00ZengNature Publishing GroupCell Death Discovery2058-77162024-11-0110111310.1038/s41420-024-02243-5NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitinationZhen Chen0Weilong Wang1Jinghan Hou2Can Gao3Meili Song4Zijun Zhao5Ruirui Guan6Jingsheng Chen7Huicheng Wu8Siti Razila Abdul Razak9Tao Han10Junbo Zhang11Lidong Wang12Nor Hazwani Ahmad13Xiumin Li14Department of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200 Kepala BatasDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineDepartment of Surgery, the Third Affiliated Hospital of Xinxiang Medical UniversityState Key Laboratory of Esophageal Cancer Prevention & Treatment and Henan Key Laboratory for Esophageal Cancer Research of The First Affiliated Hospital, Zhengzhou UniversityDepartment of Biomedical Science, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam 13200 Kepala BatasDepartment of Gastroenterology, the First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Tumor Molecular Therapy MedicineAbstract The oncogene xCT plays an indispensable role in tumor growth by protecting cancer cells from oxidative stress and ferroptosis. Emerging evidence indicated xCT function is tightly controlled by posttranslational modifications, especially ubiquitination. However, it still remains unclear what specific regulatory mechanism of xCT by ubiquitin ligases in human cancers. Here, we reported that NEDD4L, an E3 ubiquitin ligases, inhibited esophageal squamous cell carcinoma (ESCC) tumor growth and facilitated ferroptosis by ubiquitination of xCT. NEDD4L expression was declined in ESCC and was associated with tumor invasion, lymph node metastasis and distant metastasis. Silencing NEDD4L triggered ESCC tumor growth. Meanwhile, knock down of NEDD4L prevented the accumulation of ROS, elevated the level of GSH, reduced the content of MDA in ESCC cells, thereby inhibiting ferroptosis. Mechanistically, NEDD4L directly bound to the ∆CT domain of xCT through its WW and HECT domain. More importantly, NEDD4L promoted xCT degradation by facilitating its polyubiquitination in ESCC cells. Collectively, these findings suggest that NEDD4L is crucial in governing the stability of xCT and mediating ferroptosis in ESCC.https://doi.org/10.1038/s41420-024-02243-5 |
| spellingShingle | Zhen Chen Weilong Wang Jinghan Hou Can Gao Meili Song Zijun Zhao Ruirui Guan Jingsheng Chen Huicheng Wu Siti Razila Abdul Razak Tao Han Junbo Zhang Lidong Wang Nor Hazwani Ahmad Xiumin Li NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination Cell Death Discovery |
| title | NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination |
| title_full | NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination |
| title_fullStr | NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination |
| title_full_unstemmed | NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination |
| title_short | NEDD4L contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xCT ubiquitination |
| title_sort | nedd4l contributes to ferroptosis and cell growth inhibition in esophageal squamous cell carcinoma by facilitating xct ubiquitination |
| url | https://doi.org/10.1038/s41420-024-02243-5 |
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