Activation of the Enhancer of Zeste Homologue 2 Gene by the Human Papillomavirus E7 Oncoprotein

作者：Holland Daniela; Hoppe Seyler Karin; Schuller Bettina; Lohrey Claudia; Maroldt Julia; Duerst Matthias; Hoppe Seyler Felix^*

来源：Cancer Research, 2008, 68(23): 9964-9972.

DOI：10.1158/0008-5472.CAN-08-1134

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 G(1)-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]

• 出版日期2008-12-1