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Cancer Res. 2008 Dec 1;68(23):9964-72. doi: 10.1158/0008-5472.CAN-08-1134.

Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein.

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Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, Heidelberg, Germany.

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  • Cancer Res. 2009 Apr 15;69(8):3721.


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.

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