Epstein-Barr Virus Down-Regulates Tumor Suppressor DOK1 Expression

PLoS Pathogens

Henri Gruffat¹  Massimo Tommasino²  Zdenko Herceg³  Evelyne Manet⁴  Rosita Accardi⁵  Jiping Yue⁵  Cyrille Cuenin⁵  Cecilia Frecha⁵  Maha Siouda⁵  Bakary S. Sylla⁶ 

[1] CIRI, International Center for Infectiology Research, Oncogenic Herpesviruses Team, Université de Lyon, Lyon, France;CNRS, UMR5308, Lyon, France;Ecole Normale Supérieure de Lyon, Lyon, France;Inserm, U1111, Lyon, France;International Agency for Research on Cancer, World Health Organization, Lyon, France;Université Lyon 1, Centre International de Recherche en Infectiologie, Lyon, France

关键词: DNA methylation;    B cells;    Transcription factors;    Gene expression;    Polymerase chain reaction;    Epstein-Barr virus;    Viral gene expression;    Tumor suppressor genes;   

DOI  :  10.1371/journal.ppat.1004125

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY