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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / genetics
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Breast Neoplasms / genetics
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Breast Neoplasms / pathology
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Breast Neoplasms / virology
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Cell Line, Tumor
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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Enhancer of Zeste Homolog 2 Protein
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Female
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Gene Expression Regulation, Neoplastic
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Gene Silencing
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HeLa Cells
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Human papillomavirus 16 / genetics
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Human papillomavirus 18 / genetics
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Humans
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Neoplasms / genetics*
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Neoplasms / pathology
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Neoplasms / virology*
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Oncogene Proteins, Viral / genetics*
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Osteosarcoma / genetics
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Osteosarcoma / pathology
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Osteosarcoma / virology
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Papillomavirus E7 Proteins
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Polycomb Repressive Complex 2
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Promoter Regions, Genetic
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RNA, Small Interfering / genetics
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Repressor Proteins / genetics
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Transcription Factors / biosynthesis
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Transcription Factors / genetics*
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Transcription, Genetic
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / pathology
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Uterine Cervical Neoplasms / virology
Substances
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DNA-Binding Proteins
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E6 protein, Human papillomavirus type 16
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E6 protein, Human papillomavirus type 18
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E7 protein, Human papillomavirus type 18
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Oncogene Proteins, Viral
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Papillomavirus E7 Proteins
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RNA, Small Interfering
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Repressor Proteins
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Transcription Factors
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oncogene protein E7, Human papillomavirus type 16
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EZH2 protein, human
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Enhancer of Zeste Homolog 2 Protein
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Polycomb Repressive Complex 2