Zhou Qing, Yu Hongfei, Dong Anliang, Yi Jiani, Li Jia, Li Xufan, Zhou Liyuan, Qiu Qiongzi, Lu Bingjian, Zhang Honghe, Lu Weiguo, Sun Yi, Liu Pengyuan, Lu Yan
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.
Research 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.
Neoplasia. 2025 Sep;67:101211. doi: 10.1016/j.neo.2025.101211. Epub 2025 Jul 17.
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 CRL4 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.
高危型人乳头瘤病毒（HPV）的持续感染是宫颈癌发生的主要原因。尽管HPV癌蛋白E6和E7通过使p53和Rb通路失活明确引发宫颈肿瘤发生，但p53/Rb失活的下游介质仍不清楚。在此，我们报告称，Cullin-RING连接酶4（CRL4）的一个亚基CDT2在宫颈癌组织中显著上调，这与E6/E7表达及患者不良生存相关。从机制上讲，E7介导的Rb降解上调E2F1，进而增加CDT2转录，而E6介导的p53降解下调TRIM22（一种用于CDT2降解的新型E3连接酶），导致CDT2积累以促进宫颈癌细胞的生长和存活。重要的是，CDT2缺失通过稳定组蛋白赖氨酸甲基转移酶SET8（一种CRL4底物，起肿瘤抑制作用）诱导DNA非整倍性和衰老。总体而言，TRIM22-CDT2-SET8轴是p53/Rb信号在调节HPV阳性宫颈癌细胞生长和存活中的关键介质，因此，CDT2可作为这些癌症的预后生物标志物和治疗靶点。
