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.

• Authors: Daniela Holland, Karin Hoppe-Seyler, Bettina Schuller, Claudia Lohrey, Julia Maroldt, Matthias Dürst, Felix Hoppe-Seyler
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 23 Pg. 9964-72 (Dec 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 19047178 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• E6 protein, Human papillomavirus type 16
• E6 protein, Human papillomavirus type 18
• E7 protein, Human papillomavirus type 18
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• RNA, Small Interfering
• Repressor Proteins
• Transcription Factors
• oncogene protein E7, Human papillomavirus type 16
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2

Topics

• Apoptosis (genetics)
• Breast Neoplasms (genetics, pathology, virology)
• Cell Line, Tumor
• DNA-Binding Proteins (biosynthesis, genetics)
• Enhancer of Zeste Homolog 2 Protein
• Female
• Gene Expression Regulation, Neoplastic
• Gene Silencing
• HeLa Cells
• Human papillomavirus 16 (genetics)
• Human papillomavirus 18 (genetics)
• Humans
• Neoplasms (genetics, pathology, virology)
• Oncogene Proteins, Viral (genetics)
• Osteosarcoma (genetics, pathology, virology)
• Papillomavirus E7 Proteins
• Polycomb Repressive Complex 2
• Promoter Regions, Genetic
• RNA, Small Interfering (genetics)
• Repressor Proteins (genetics)
• Transcription Factors (biosynthesis, genetics)
• Transcription, Genetic
• Uterine Cervical Neoplasms (genetics, pathology, virology)