The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells
Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elus...
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Elsevier
2025-09-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558625000892 |
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| author | Qing Zhou Hongfei Yu Anliang Dong Jiani Yi Jia Li Xufan Li Liyuan Zhou Qiongzi Qiu Bingjian Lu Honghe Zhang Weiguo Lu Yi Sun Pengyuan Liu Yan Lu |
| author_facet | Qing Zhou Hongfei Yu Anliang Dong Jiani Yi Jia Li Xufan Li Liyuan Zhou Qiongzi Qiu Bingjian Lu Honghe Zhang Weiguo Lu Yi Sun Pengyuan Liu Yan Lu |
| author_sort | Qing Zhou |
| collection | DOAJ |
| description | Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elusive. Here we report that CDT2, a subunit of Cullin-RING ligase 4 (CRL4), is significantly upregulated in cervical carcinoma tissues, which correlates with E6/E7 expression and poor patient survival. Mechanistically, E7-mediated Rb degradation upregulates E2F1, which in turn increases CDT2 transcription, whereas E6-mediated p53 degradation downregulates TRIM22, a novel E3 ligase for CDT2 degradation, leading to CDT2 accumulation to promote growth and survival of cervical cancer cells. Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4CDT2 substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas. |
| format | Article |
| id | doaj-art-f2bd8a632eff4f5daf40c5c077f5bb5f |
| institution | DOAJ |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-f2bd8a632eff4f5daf40c5c077f5bb5f2025-08-20T02:45:14ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-09-016710121110.1016/j.neo.2025.101211The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cellsQing Zhou0Hongfei Yu1Anliang Dong2Jiani Yi3Jia Li4Xufan Li5Liyuan Zhou6Qiongzi Qiu7Bingjian Lu8Honghe Zhang9Weiguo Lu10Yi Sun11Pengyuan Liu12Yan Lu13Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR ChinaResearch Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, PR China; Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR ChinaZhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR ChinaKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR ChinaKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR ChinaKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR ChinaKey Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR ChinaZhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR ChinaZhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR ChinaDepartment of Pathology, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, PR ChinaZhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR ChinaResearch Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, PR China; Cancer Institute of the 2nd Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, PR China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, PR China; Corresponding authors.Key Laboratory of Precision Medicine in Diagnosis and Monitoring Research of Zhejiang Province, Sir Run Run Shaw Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, PR China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, PR China; Corresponding authors.Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Department of Gynecologic Oncology, Women’s Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310013, PR China; Corresponding authors.Persistent infection with high-risk human papillomavirus (HPV) is the primary contributor to the development of cervical cancer. Although HPV oncoproteins E6 and E7 clearly trigger cervical tumorigenesis by inactivating p53 and Rb pathways, the downstream mediators of p53/Rb inactivation remain elusive. Here we report that CDT2, a subunit of Cullin-RING ligase 4 (CRL4), is significantly upregulated in cervical carcinoma tissues, which correlates with E6/E7 expression and poor patient survival. Mechanistically, E7-mediated Rb degradation upregulates E2F1, which in turn increases CDT2 transcription, whereas E6-mediated p53 degradation downregulates TRIM22, a novel E3 ligase for CDT2 degradation, leading to CDT2 accumulation to promote growth and survival of cervical cancer cells. Importantly, CDT2 depletion induces DNA aneuploidy and senescence via stabilization of histone lysine methyltransferase SET8, a CRL4CDT2 substrate, acting as a tumor suppressor. Collectively, the TRIM22-CDT2-SET8 axis is the key mediator of the p53/Rb signals in regulation of growth and survival of HPV-positive cervical carcinoma cells, Thus, CDT2 could serve as a prognostic biomarker and therapeutic target for these carcinomas.http://www.sciencedirect.com/science/article/pii/S1476558625000892Cervical cancerCDT2HPVsenescenceTRIM22SET8 |
| spellingShingle | Qing Zhou Hongfei Yu Anliang Dong Jiani Yi Jia Li Xufan Li Liyuan Zhou Qiongzi Qiu Bingjian Lu Honghe Zhang Weiguo Lu Yi Sun Pengyuan Liu Yan Lu The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells Neoplasia: An International Journal for Oncology Research Cervical cancer CDT2 HPV senescence TRIM22 SET8 |
| title | The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells |
| title_full | The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells |
| title_fullStr | The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells |
| title_full_unstemmed | The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells |
| title_short | The TRIM22-CDT2 axis is the key mediator of the p53-Rb signals in growth control of HPV-positive cervical carcinoma cells |
| title_sort | trim22 cdt2 axis is the key mediator of the p53 rb signals in growth control of hpv positive cervical carcinoma cells |
| topic | Cervical cancer CDT2 HPV senescence TRIM22 SET8 |
| url | http://www.sciencedirect.com/science/article/pii/S1476558625000892 |
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