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

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.

Keywords: DNA methylation; EBV-associated gastric cancer; EBV-associated lymphomas; Epstein-Barr virus; epigenetics; histone modifications; nasopharyngeal carcinoma.

Figure 1

A schematic diagram shows the impact of EBV on epigenetic dysregulation in NPC. LMP1 activates JNK and NFκB signaling pathways to enhance expression of DNMTs, resulting in promoter DNA hypermethylation in the TSGs including CDH1 (encoding E-cadherin) and PTEN. LMP1 may also promote phosphorylation of ERK1/2, resulting in phosphorylation of H3Ser10 to activate the expression of AP-1. Up-regulation of EBNA1 inhibits DDR genes expression probably through dysregulating bivalent switches in NPE cell lines.

Figure 2

A schematic diagram shows the impact of EBV on epigenetic dysregulation in EBVaGC. LMP2A inhibits TET2 and activates STAT3 and ERK signaling pathways to enhance expression of DNMTs, resulting in promoter DNA hypermethylation to suppress gene expression including PTEN and AQP3. EBNA1 enhanced the expression of ATF3, which functions as a transcription factor, to promote target gene expression, characterized by gain of H3K27ac. EBV can also interact with the host genome, where A-T content is enriched as well as H3K4me1 and H3K27ac, and reduced H3K9me3 levels to promote gene expression.

Figure 3

A schematic diagram shows the impact of EBV on epigenetic dysregulation in EBV-associated lymphomas. LMP1 and NFκB are required to suppress the expression of ID3 via promoter methylation by a recruitment of the DNMT complex. EBNA3C promotes expression of DNMT3a to induce DNA methylation, resulting in suppression of gene expression including RASSF1. EBNA3C also interacts with EBNA3A to regulate the histone bivalent switch to recruit EZH2 and SUZ12 to the BIM promoter to regulate the expression, with evidence of the relevant promoter methylation. The EBV C promoter (Cp), W promoter (Wp), and LMP promoter (LMPp) are restricted by the host factors, including DNMT1 and UHRF1, through DNA methylation, or mono-ubiquitination of the LMPp by PRC1 (Ub: H2AK119Ub1). The interactions of EBV and host genome, through EBNA1 tethering, are associated with gene silencing and enriched with enhanced H3K9me3, A-T content, RBP-jK, and EBF1.