Activation of the Enhancer of Zeste Homologue 2 Gene by the Human Papillomavirus E7 Oncoprotein
2008; American Association for Cancer Research; Volume: 68; Issue: 23 Linguagem: Inglês
10.1158/0008-5472.can-08-1134
ISSN1538-7445
AutoresDaniela Holland, Karin Hoppe‐Seyler, Bettina Schuller, Claudia Lohrey, Julia Maroldt, Matthias Dürst, Felix Hoppe‐Seyler,
Tópico(s)Cervical Cancer and HPV Research
ResumoAbstract The malignant phenotype of human papillomavirus (HPV)-positive cancer cells is maintained by the activity of the viral E6 and E7 genes. Here, we identified the polycomb group gene enhancer of zeste homologue 2 (EZH2) as a novel downstream target for the viral oncogenes in HPV-transformed cells. EZH2 expression was activated by HPV16 E7 at the transcriptional level via E7-mediated release of E2F from pocket proteins. RNA interference analyses showed that continuous EZH2 expression is required for the proliferation of HPV-positive tumor cells by stimulating cell cycle progression at the G1-S boundary. In addition to its growth-promoting activity, EZH2 also contributed to the apoptotic resistance of cervical cancer cells. Furthermore, we found that HPV-positive dysplastic and tumorigenic cervical lesions were characterized by high levels of EZH2 protein in vivo. We conclude that the E7 target gene EZH2 is a major determinant for the proliferation of HPV-positive cancer cells and contributes to their apoptotic resistance. Moreover, EZH2 may serve as a novel therapeutic target for the treatment of cervical cancer. [Cancer Res 2008;68(23):9964–72]
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