Viral driven epigenetic events alter the expression of cancer-related genes in Epstein-Barr-virus naturally infected Burkitt lymphoma cell lines

Abstract

Epstein-Barr virus (EBV) was identified as the first human virus to be associated with a human malignancy, Burkitt’s lymphoma (BL), a pediatric cancer endemic in sub-Saharan Africa. The exact mechanism of how EBV contributes to the process of lymphomagenesis is not fully understood. Recent studies have highlighted a genetic difference between endemic (EBV+) and sporadic (EBV−) BL, with the endemic variant showing a lower somatic mutation load, which suggests the involvement of an alternative virally-driven process of transformation in the pathogenesis of endemic BL. We tested the hypothesis that a global change in DNA methylation may be induced by infection with EBV, possibly thereby accounting for the lower mutation load observed in endemic BL. Our comparative analysis of the methylation profiles of a panel of BL derived cell lines, naturally infected or not with EBV, revealed that the presence of the virus is associated with a specific pattern of DNA methylation resulting in altered expression of cellular genes with a known or potential role in lymphomagenesis. These included ID3, a gene often found to be mutated in sporadic BL. In summary this study provides evidence that EBV may contribute to the pathogenesis of BL through an epigenetic mechanism.

Interplay between the epigenetic enzyme lysine (K)-specific demethylase 2B and Epstein-Barr virus infection

“…Our comparative analysis of the whole genome methylation profiles of a set of EBV (+) and EBV (-) Burkitt’s lymphoma derived cell lines (4), led to identification of two CpGs (CpG 15695155 and 21423404) in an intragenic putative regulatory region of KDM2B (Fig 1A) highly methylated in EBV (+) BL derived cells. To validate these data we performed direct pyrosequencing on DNA extracted from 7 BL EBV (+) BL and 7 EBV (-) BL derived cell lines and confirmed that KDM2B gene is hyper-methylated at CpG 15695155 and 21423404 in EBV (+) BL cell lines compared to EBV (–) BL cell lines (Figure 1B).…”

“…Increasing evidence argues that different viruses may abrogate cellular defense systems by hijacking epigenetic mechanisms to deregulate host cell gene expression program and modulate their own life cycle (2, 3). Our recent study of the methylome profiles of sporadic- versus endemic-derived BL cell lines revealed EBV infection-specific pattern of methylation, with aberrant methylation in genes with a known role in lymphomagenesis, such as ID3, often found mutated in sporadic BL (sBL) (4). We therefore hypothesized that a viral-driven mechanism is responsible for modifying the epigenome of B-cells to facilitate the lymphomagenic process, circumventing the need for mutations in lymphoma driver genes.…”

DNA methyltransferases in virus‐associated cancers

“…Moreover, impairing mutations in repressive function of ID3 results in B‐cell signaling activation and lymphoid proliferation . In 2017, a published study revealed that LMP1 promotes promoter methylation and silencing of ID3 expression via enhancing recruitment of the DNMTs during the EBV infection in B cells . Paschos and colleagues attempted to display the relation between EBV latency and suppression of tumor suppressor gene Bim.…”

“…Epstein-Barr virus (EBV) was the first human virus that was found to be associated with a variety of human malignancies with origin of lymphoid or epithelial including Burkitt's lymphoma (BL), nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), posttransplant lymphoproliferative disease (PTLD), and Hodgkin's lymphoma (HL). 44,45 Pathogenesis of EBV-associated cancers (EBVaC) seems to be correlated with role of the virus as a direct epigenetic driver. 46,47 EBV encodes two latent phase proteins named LMP-1 and LMP-2 that are considered as oncogenic elements with crucial role in tumor transformation that affect epithelial and lymphoid cells.…”

“…71,72 In 2017, a published study revealed that LMP1 promotes promoter methylation and silencing of ID3 expression via enhancing recruitment of the DNMTs during the EBV infection in B cells. 45 Paschos and colleagues attempted to display the relation between EBV latency and suppression of tumor suppressor gene Bim. For this purpose, they used DNMT inhibitor 5′ azacytidine and observed derepression of Bim in EBV-positive BL biopsies.…”