The roles of DNA methylation on the promotor of the Epstein–Barr virus (EBV) gene and the genome in patients with EBV-associated diseases

Abstract

Epstein–Barr virus (EBV) is an oncogenic virus that is closely associated with several malignant and lymphoproliferative diseases. Studies have shown that the typical characteristic of EBV-associated diseases is aberrant methylation of viral DNA and the host genome. EBV gene methylation helps EBV escape from immune monitoring and persist in host cells. EBV controls viral gene promoter methylation by hijacking host epigenetic machinery to regulate the expression of viral genes. EBV proteins also interact with host epigenetic regulatory factors to mediate the methylation of the host’s important tumour suppressor gene promoters, thereby participating in the occurrence of tumorigenesis. Since epigenetic modifications, including DNA methylation, are reversible in nature, drugs that target DNA methylation can be developed for epigenetic therapy against EBV-associated tumours. Various methylation modes in the host and EBV genomes may also be of diagnostic and prognostic value. This review summarizes the regulatory roles of DNA methylation on the promotor of EBV gene and host genome in EBV-associated diseases, proposes the application prospect of DNA methylation in early clinical diagnosis and treatment, and provides insight into methylation-based strategies against EBV-associated diseases. Key points • Methylation of both the host and EBV genomes plays an important role in EBV-associateddiseases. • The functions of methylation of the host and EBV genomes in the occurrence and development of EBV-associated diseases are diverse. • Methylation may be a therapeutic target or biomarker in EBV-associated diseases.

Quantitative detection of Epstein‐Barr virus DNA methylation in the diagnosis of nasopharyngeal carcinoma by blind brush sampling

“…EBV DNA is unmethylated within the virion, while it becomes methylated when entering infected cells 38 . Among which, an important regulator is the methylation of C‐promoter region 39 . Unmethylation was predominant in most samples from control group (Table S7).…”

“…38 Among which, an important regulator is the methylation of C-promoter region. 39 Unmethylation was predominant in most samples from control group (Table S7). It seemed most of the EBV DNA in the samples was probably from free EBV virion.…”

The viral etiology of EBV-associated gastric cancers contributes to their unique pathology, clinical outcomes, treatment responses and immune landscape

“…Based on the CpG-island methylator phenotype (CIMP), EBVaGCs belong to the high (CIMP-H) category ( 129 , 151 ). In fact, over 1000 genes have been found to be differentially methylated by EBV, with hypermethylated genes enriched in Wnt and protein kinase signalling pathways, among other cancer-associated pathways ( 152 – 154 ). EBV is also noted to express a number of miRNAs, with said miRNAs functioning to inhibit pro-apoptotic genes and promote cell survival, as well as regulate the expression of EBV-associated genes ( 115 , 155 ).…”

“…Another drug currently undergoing clinical trials, zebularine, was previously shown to demethylate the STING promoter, which regulates expression of the cGAS/STING innate immune pathway, resulting in increased CD8+ T and NK infiltration, as well as reduced tumor burden in GC cell line-based models ( 283 ). The benefits of these classes of drugs include the reversibility of effects, due to epigenetic changes, as well the possibility of reversing changes in the TME ( 154 , 284 ). Downsides of such drugs include the potential of non-specific gene activation as a result of demethylation, which may include oncogenes, as well as the lack of studies exploring the long-term effects of epigenetic therapies ( 129 ).…”

Role of plasma EBV-DNA load and EBER status on newly diagnosed peripheral T-cell lymphoma

“…Hypomethylating agents, such as azacytidine (AZA), have the potential to reduce genomic methylation levels and reactivate hypermethylated tumor suppressor genes. Therefore, targeting DNA methylation may represent a novel therapeutic strategy for EBV-associated diseases (Zhang et al 2022 ).…”