Epigenetic dysregulation of the host cell genome in Epstein–Barr virus-associated neoplasia

Abstract

Epstein–Barr virus (EBV), a human herpesvirus, is associated with a wide variety of malignant tumors. The expression of the latent viral RNAs is under strict, host-cell dependent transcriptional control. This results in an almost complete transcriptional silencing of the EBV genome in memory B-cells. In tumor cells, germinal center B-cells and lymphoblastoid cells, distinct viral latency promoters are active. Epigenetic mechanisms contribute to this strict control. In EBV-infected cells, epigenetic mechanisms also alter the expression of cellular genes, including tumor suppressor genes. In Nasopharyngeal Carcinoma, the hypermethylation of certain cellular promoters is attributed to the upregulation of DNA methyltransferases by the viral oncoprotein LMP1 (latent membrane protein 1) via JNK/AP1-signaling. The role of other viral latency products in the epigenetic dysregulation of the cellular genome remains to be established. Analysis of epigenetic alterations in EBV-associated neoplasms may result in a better understanding of their pathogenesis and may facilitate the development of new therapies.

Introduction

Epstein–Barr virus (EBV) is the first virus associated with a human neoplasm. The discovery of the virus by electron microscopy in explants from Burkitt's Lymphoma (BL), an endemic childhood tumor mainly of equatorial Africa was the first strong lead towards human tumor virology. Shortly after, seroepidemiological studies revealed a general association of EBV with endemic BL and undifferentiated Nasopharyngeal Carcinoma (NPC), a lymphoepithelial tumor endemic mainly in South East Asia. Concurrently, EBV was found to be the pathogenic agent of infectious mononucleosis (IM), when a lab technician of the Henle laboratory experienced an IM and consequently developed EBV-specific antibodies. Due to its causal role in IM and its association with BL, EBV was considered a strictly lymphotropic virus. In the following, the EBV genome was also detected in BL- and NPC-biopsies, by nucleic acid hybridization to DNA from BL and NPC biopsies, to individual NPC tumor cells in situ and to purified NPC tumor cell fractions, but not to the great many reactive infiltrating lymphocytes [1], [2]. The association with an epithelial tumor changed the appreciation of the role of EBV substantially. Before long, further EBV-related malignancies followed: post-transplant lymphoma (PTL), Hodgkin's Disease (HD), NK or T-cell lymphomas, gastric carcinoma (GAC), and leiomyosarcoma (for review see [3] and references therein). Furthermore, EBV was linked to a series of common autoimmune diseases [4]. The EBV-link to multiple sclerosis has become stronger recently, through the detection of latently infected B-cells in ectopic lymphoid follicles and acute lesions of the MS brain [5].

Epigenetic mechanisms play an essential role in gene regulation, development and tissue differentiation. Well known epigenetic modifications, like the C5-methylation at CpG dinucleotides, and the covalent histone modification through the attachment of acetyl-, methyl-, or phosphate groups, lead to the silencing or activation of promoters. Epigenetic dysregulation contributes to the onset of cancer. The overall degree of DNA methylation decreases with tumor progression. However, the methylation frequency at CpG islands (CGIs) and histone modifications increase. CGI methylation is now considered a hallmark of cancer in general. Epigenetic imbalance of oncogenes and tumor suppressor genes (TSGs) has been found in a large series of tumors. Actually, TSGs are more frequently inactivated by methylation than by mutation [6]. Epigenetic dysregulation frequently precedes carcinogenesis, and several carcinoma types are surrounded by a large epithelial zone carrying epigenetic anomalies. The presence of an epigenetic field for cancerization has been indicated for liver, colon, gastric, Barrett's esophageal, lung, breast and renal cancers [7]. CpG methylation may be used as a marker for carcinogen exposure, as a prognostic predictor, and as a therapeutic target. In this paper, we focus on the epigenetic disruptions of EBV-associated lymphomas and carcinomas.