Herpesvirus Epigenetic Reprogramming and Oncogenesis

Abstract

Among all of the known biological carcinogens, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are two of the classical oncogenic herpesviruses known to induce the oncogenic phenotype. Many studies have revealed important functions related to epigenetic alterations of the EBV and KSHV genomes that mediate oncogenesis, but the detailed mechanisms are not fully understood. It is also challenging to fully describe the critical cellular events that drive oncogenesis as well as a comprehensive map of the molecular contributors. This review introduces the roles of epigenetic modifications of these viral genomes, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA expression, and elucidates potential strategies utilized for inducing oncogenesis by these human gammaherpesviruses.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…EBV-associated cancers such as gastric cancer, nasopharyngeal carcinoma and Burkitt’s lymphoma are characterized by extensive hypermethylation of the host DNA compared with non-infected tumors and cell culture studies have illustrated that EBV infection induces de novo methylation [ 45 , 111 , 118 , 119 , 120 , 121 , 122 ]. Many of the genes whose expression is affected by EBV-induced methylation code for proteins involved in cell cycle control, signaling pathways, apoptosis, invasion and migration [ 45 , 111 , 122 , 123 ]. Some of these genes will be discussed, as well as the viral proteins involved in their methylation.…”

“…Some of the genes that were hypermethylated in KSHV-infected PEL cell lines included CDNK2A , CDH1 and CDH13 (cadherin 1 and 13), LDHB (lactate dehydrogenase B), HLTF (helicase like transcription factor, a member of the chromatin remodeling SWI/SNF family), CCND2 (cyclin D2). The authors showed that KHSV LANA recruited DNMT3A to chromatin, and induced hypermethylation and transcriptional inactivation of these genes [ 43 , 44 , 45 ]. LANA may not only repress transcription of cellular genes by inducing hypermethylation, but it may potentiate transcriptional inhibition through recruiting the transcriptional repressor methyl CpG binding protein 2 (MeCP2), which interacts with LANA [ 46 ].…”

“…The EBV BHRF1 cluster and the BamHI-A rightward transcript (BART) clusters 1 and 2 encode >40 mature miRs, which can regulate host and viral gene expression. These viral miRs are crucial for EBV-associated tumorigenesis by e.g., inhibiting apoptosis, immune evasion, and cell growth [ 45 , 247 , 248 , 249 ]. For example, EBV miR-BART2-5p silences MHC class I polypeptide-related sequence B (MCIB) expression to inhibit natural killer cell recognition and activation, allowing immune evasion of the EBV-positive tumor cell.…”

“…KSHV produces 25 mature microRNAs and more than 2000 host transcripts that encode proteins associated with KSHV pathogenesis can be directly targeted by these viral microRNAs [ 250 , 287 , 288 ]. The functions of KSHV microRNAs have been extensively studied and showed that they perturbed expression of host proteins, which are involved in angiogenesis, proliferation, cell survival, migration and invasion, and immune evasion [ 45 , 247 , 248 , 250 , 251 , 288 ]. A few examples are mentioned.…”

Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

“…For most individuals, lifelong EBV colonization of the memory B-cell compartment is asymptomatic. Nonetheless, EBV is associated with 200,000 human cancers per year, including Burkitt lymphoma, post-transplant lymphoproliferative diseases, Hodgkin lymphoma, gastric and nasopharyngeal carcinoma (1,2). Endemic Burkitt lymphoma caused by EBV remains the most common childhood cancer in sub-Saharan Africa (3)(4)(5).…”