title: Epstein-Barr virus down-regulates tumor suppressor DOK1 expression.
abstract: The DOK1 tumor suppressor gene encodes an adapter protein that acts as a negative regulator of several signaling pathways. We have previously reported that DOK1 expression is up-regulated upon cellular stress, via the transcription factor E2F1, and down-regulated in a variety of human malignancies due to aberrant hypermethylation of its promoter. Here we show that Epstein Barr virus (EBV) infection of primary human B-cells leads to the down-regulation of DOK1 gene expression via the viral oncoprotein LMP1. LMP1 alone induces recruitment to the DOK1 promoter of at least two independent inhibitory complexes, one containing E2F1/pRB/DNMT1 and another containing at least EZH2. These events result in tri-methylation of histone H3 at lysine 27 (H3K27me3) of the DOK1 promoter and gene expression silencing. We also present evidence that the presence of additional EBV proteins leads to further repression of DOK1 expression with an additional mechanism. Indeed, EBV infection of B-cells induces DNA methylation at the DOK1 promoter region including the E2F1 responsive elements that, in turn, lose the ability to interact with E2F complexes. Treatment of EBV-infected B-cell-lines with the methyl-transferase inhibitor 5-aza-2'-deoxycytidine rescues DOK1 expression. In summary, our data show the deregulation of DOK1 gene expression by EBV and provide novel insights into the regulation of the DOK1 tumor suppressor in viral-related carcinogenesis.
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Maha
authors.initials: M
authors.lastname: Siouda
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Frecha
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Rosita
authors.initials: R
authors.lastname: Accardi
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Jiping
authors.initials: J
authors.lastname: Yue
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Cyrille
authors.initials: C
authors.lastname: Cuenin
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses Team, Université de Lyon, Lyon, France; Inserm, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, Lyon, France.
authors.forename: Henri
authors.initials: H
authors.lastname: Gruffat
authors.affiliation: CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses Team, Université de Lyon, Lyon, France; Inserm, U1111, Lyon, France; Ecole Normale Supérieure de Lyon, Lyon, France; Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France; CNRS, UMR5308, Lyon, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Manet
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Bakary S
authors.initials: BS
authors.lastname: Sylla
authors.affiliation: International Agency for Research on Cancer, World Health Organization, Lyon, France.
authors.forename: Massimo
authors.initials: M
authors.lastname: Tommasino
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002472:Cell Transformation, Viral / Q000235:genetics; D002478:Cells, Cultured; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D014763:Viral Matrix Proteins