Epstein-Barr Virus Down-Regulates Tumor Suppressor Expression

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Many oncogenic viruses exhibit cellular transforming properties, often involving oncogenes activation and tumor suppressor genes inactivation. The DOK1 gene is a newly identified tumor suppressor gene with altered expression via hypermethylation of its promoter in a variety of human cancers, including head and neck, lung, gastric and others. In addition, a correlation has been reported between DOK1 aberrant hypermethylation and the presence of oncogenic viruses such as hepatitis B virus (HBV) in hepatocellular carcinoma (HCC) and Epstein-Barr virus (EBV) in Burkitt's lymphoma-derived cell lines. Here we demonstrate for the first time that EBV is directly involved in the inhibition of DOK1 expression in B-cells. We show that EBV leads to epigenetic repression of DOK1 through increased DNA methylation of its promoter and H3K27 tri-methylation. The LMP1 oncoprotein plays a key role in the repression of DOK1 expression. It promotes the formation and the recruitment to the DOK1 promoter of transcriptionally inhibitory complexes composed of E2F1/pRB/DNMT1 and of EZH2 which is part of the polycomb repressive complex 2. Interestingly, one or more additional EBV protein(s) cooperate(s) with LMP1 in inducing massive DNA methylation at the DOK1 promoter, leading to the loss of E2F1 complexes recruitment and even stronger repression of DOK1 expression.

Vyšlo v časopise: Epstein-Barr Virus Down-Regulates Tumor Suppressor Expression. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004125
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004125

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