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Activation of the Enhancer of Zeste Homologue 2 Gene by the Human Papillomavirus E7 Oncoprotein
Abstract
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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“HPV-16 E7 has also been shown to induce expression of H3K27 histone methyltransferase EZH2 (enzymatic component of PRC2), enhancing PRC4 complex formation [337], which has been demonstrated to cause histone H1K26 deacetylation and methylation [338]”
From The Not-So-Good, the Bad and the Ugly: HPV E5, E6 and E7 Oncoproteins in the Orchestration of Carcinogenesis (2021) · cites this paper as [337]
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The polycomb group protein EZH2 is involved in progression of prostate cancer
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EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer.
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“Similarly, siRNA treatment of nontumorigenic breast epithelial MCF-10A cells did not induce apoptosis; however, it led to increased apoptosis in MCF-7 breast cancer cells (39).”
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Cited by
Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders
Ernst, T., Chase, A. J., Score, J., Hidalgo-Curtis, C. E., Bryant, C., Jones, A. V., Waghorn, K., Zoi, K., Ross, F. M., Reiter, A., et al. (2010) · Nature Genetics · doi:10.1038/ng.621 · Cited by 1,139
Basukala, O., & Banks, L. (2021) · Viruses · doi:10.3390/v13101892 · Cited by 137
Metadata
- Authors
- Holland, D., Hoppe-Seyler, K., Schuller, B., Lohrey, C., Maroldt, J., Dürst, M., & Hoppe-Seyler, F.
- Affiliations
- 1Molecular Therapy of Virus-Associated Cancers (F065), German Cancer Research Center, Heidelberg, Germany and
- 2Gynäkologische Molekularbiologie, Frauenklinik der FSU Jena, Jena, Germany
- Venue
- Cancer Research
- Published
- 2008-12-01
- Volume
- 68
- Issue
- 23
- Pages
- 9964-9972
- ISSN
- 0008-5472
- 1538-7445
- Cited by
- 99
- References
- 7
- Language
- en
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- Holland, D., Hoppe-Seyler, K., Schuller, B., Lohrey, C., Maroldt, J., Dürst, M., & Hoppe-Seyler, F. (2008). Activation of the Enhancer of Zeste Homologue 2 Gene by the Human Papillomavirus E7 Oncoprotein. Cancer Research. https://doi.org/10.1158/0008-5472.can-08-1134