Abstract
EZH2 is a component of the epigenetic regulator PRC2 that suppresses gene expression. Elevated expression of EZH2 is common in human cancers and is associated with tumor progression and poor prognosis. In this study, we show that EZH2 elevation is associated with epigenetic modifications of Kaposi sarcoma-associated herpesvirus (KSHV), an oncogenic virus that promotes the development of Kaposi sarcoma and other malignancies that occur in patients with chronic HIV infections. KSHV induction of EZH2 expression was essential for KSHV-induced angiogenesis. High expression of EZH2 was observed in Kaposi sarcoma tumors. In cell culture, latent KSHV infection upregulated the expression of EZH2 in human endothelial cells through the expression of vFLIP and LANA, two KSHV-latent genes that activate the NF-κB pathway. KSHV-mediated upregulation of EZH2 was required for the induction of Ephrin-B2, an essential proangiogenic factor that drives endothelial cell tubule formation. Taken together, our findings indicate that KSHV regulates the host epigenetic modifier EZH2 to promote angiogenesis.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inducing Agents / metabolism*
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Antigens, Viral / metabolism
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Cell Line
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism*
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Endothelial Cells / metabolism
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Endothelial Cells / virology
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Enhancer of Zeste Homolog 2 Protein
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Ephrin-B2 / genetics*
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Gene Expression Regulation
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Herpesviridae Infections / genetics*
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Herpesvirus 8, Human / genetics*
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Herpesvirus 8, Human / physiology
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Humans
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NF-kappa B / metabolism
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Neovascularization, Pathologic / genetics*
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Nuclear Proteins / metabolism
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Polycomb Repressive Complex 2
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Sarcoma, Kaposi / blood supply*
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Sarcoma, Kaposi / genetics*
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Sarcoma, Kaposi / virology
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Transcription Factors / genetics*
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Transcription Factors / metabolism*
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Up-Regulation
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Viral Proteins / metabolism
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Virus Latency / genetics
Substances
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Angiogenesis Inducing Agents
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Antigens, Viral
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DNA-Binding Proteins
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Ephrin-B2
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NF-kappa B
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Nuclear Proteins
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Transcription Factors
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Viral Proteins
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latency-associated nuclear antigen
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viral FLIP protein, Human herpesvirus 8
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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