The Impact of Epstein-Barr Virus Infection on Epigenetic Regulation of Host Cell Gene Expression in Epithelial and Lymphocytic Malignancies.

Merrin Man Long Leong,Maria Li Lung

doi:10.3389/fonc.2021.629780

Abstract

Epstein-Barr virus (EBV) infection is associated with a variety of malignancies including Burkitt’s lymphoma (BL), Hodgkin’s disease, T cell lymphoma, nasopharyngeal carcinoma (NPC), and ∼10% of cases of gastric cancer (EBVaGC). Disruption of epigenetic regulation in the expression of tumor suppressor genes or oncogenes has been considered as one of the important mechanisms for carcinogenesis. Global hypermethylation is a distinct feature in NPC and EBVaGC, whereas global reduction of H3K27me3 is more prevalent in EBVaGC and EBV-transformed lymphoblastoid cells. In BL, EBV may even usurp the host factors to epigenetically regulate its own viral gene expression to restrict latency and lytic switch, resulting in evasion of immunosurveillance. Furthermore, in BL and EBVaGC, the interaction between the EBV episome and the host genome is evident with respectively unique epigenetic features. While the interaction is associated with suppression of gene expression in BL, the corresponding activity in EBVaGC is linked to activation of gene expression. As EBV establishes a unique latency program in these cancer types, it is possible that EBV utilizes different latency proteins to hijack the epigenetic modulators in the host cells for pathogenesis. Since epigenetic regulation of gene expression is reversible, understanding the precise mechanisms about how EBV dysregulates the epigenetic mechanisms enables us to identify the potential targets for epigenetic therapies. This review summarizes the currently available epigenetic profiles of several well-studied EBV-associated cancers and the relevant distinct mechanisms leading to aberrant epigenetic signatures due to EBV.

Highlights

Epstein-Barr virus (EBV), known as human herpesvirus 4, was the first human cancer-associated virus to be discovered [1]
This study showed that the presence of LMP1 elevated the level of pRB and E2F1, which may be relevant to the enhanced expression of DNA methyltransferase (DNMT), the connection of the Rb-E2F1 pathway to LMP1-mediated DNMTs activation was uncertain in nasopharyngeal carcinoma (NPC) [42]
Introducing a acetyl group to the residue neutralizes the positive charge on the lysine and weakens the electrostatic interaction between negatively charged DNA and histones, resulting in loosening of chromatin structure to be accessible to transcription factors (TFs) [78, 79]

Summary

Introduction

Epstein-Barr virus (EBV), known as human herpesvirus 4, was the first human cancer-associated virus to be discovered [1]. The significance of LMP1 contributing to DNA methylation was further highlighted by a study in which overexpression of LMP1 in a NPC cell line induced expression of DNMT1 and DNMT3a/b; all these DNMTs are necessary to suppress RARb2 via promoter hypermethylation [42].

Results

Conclusion