Abstract
Epstein-Barr virus (EBV) is a gammaherpesvirus associated with a variety of lymphoid and epithelial tumors. Although EBV is a known tumor virus, incomplete association of EBV with any given tumor type has confounded its role in tumorigenesis. For example, only 15% of gastric carcinomas are EBV-positive compared to virtually all undifferentiated nasopharyngeal carcinomas. Upon entry into a cell, the viral genome is chromatinized and EBV rapidly shuts off its viral gene expression program via methylation of its viral promoters in an attempt to evade the host immune response. A similar restricted pattern of viral gene expression is present in EBV-positive tumors. We hypothesize that EBV infection of tumor cells results in virus-induced epigenetic alterations to host genes that remain after loss of the virus and may provide a selective advantage to the tumor cell. To identify virally induced epigenetic alterations, we established a transient model of infection to model the effects of viral redundancy and loss in carcinogenesis. Carcinoma cell lines were infected with recombinant EBV, passaged with selective pressure, and allowed to lose viral genomes by withdrawal of selection. Transient EBV infection of lung carcinoma cells resulted in numerous gene expression changes relative to uninfected controls suggestive of cellular epigenetic reprogramming. Two such gene expression changes, PYCARD and E-cadherin were found to be due to DNA methylation and loss of histone acetylation, respectively. To understand the mechanism behind loss of histone acetylation at the E-cadherin locus following transient EBV infection, we examined the role of histone deacetylases (HDACs) in mediating the epigenetic repression. We observed an increase in total HDAC activity in our transiently infected, EBV-negative clones. Through the use of specific inhibitors, we noted class I HDACs, specifically HDAC1, was involved in the repression of E-cadherin in transiently infected clones. EBV-modulation of HDAC1 activity may lead to host epigenetic alterations that are retained after loss of the virus. Future experiments are aimed at determining the viral and cellular players responsible for the epigenetic alterations that are seen in transiently infected, EBV-negative clones. These results suggest that EBV alters cellular gene expression in a heritable fashion in formerly infected cells, while its own contribution to the oncogenic process is masked.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-69. doi:1538-7445.AM2012-LB-69
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
