Impact of EBV Essential Nuclear Protein EBNA-3C on B-Cell Proliferation and Apoptosis

Abstract

For over 40 years, EBV infection has been implicated in the etiology of a variety of lymphoid malignancies with the exceptional ability to drive resting B cells to continuously proliferate by successfully overriding cellular apoptotic stimuli. EBV utilizes the normal physiology of B-cell differentiation to persist within the memory B-cell pool of the immunocompetent host and subsequently establishes a lifelong latent infection. During latency, out of a subset of viral genes expressed, EBNA-3C is one of the essential antigens required for in vitro primary B-cell transformation. EBNA-3C acts as a transcriptional coregulator by interacting with various cellular and viral factors. For the last 10 years, we have been actively engaged in discerning the biological significance of these interactions and revealed that EBNA-3C primarily targets two important cellular pathways – cell cycle and apoptosis. This review aims to summarize our current knowledge on EBNA-3C-mediated functions and describe how EBNA-3C seizes these cellular pathways that eventually promote B-cell lymphomagenesis. A scrupulous understanding of the critical relationship between EBNA-3C and these cellular machineries will not only aid in elucidating EBV pathogenesis, but also largely facilitate the development of novel diagnostic, as well as therapeutic, strategies against a vast range of EBV-associated B-cell lymphomas.

Epstein-Barr Virus and Human Herpesvirus 6 Detection in a Non-Hodgkin's Diffuse Large B-Cell Lymphoma Cohort by Using RNA Sequencing

“…In the two EBV-positive DLBCL samples, SRS405439 and SRS405443, the high read numbers in conjunction with the finding of clear expression of oncogenic latency genes (23)(24)(25)(26) are consistent with an etiological role for EBV in these cases. In contrast, it is much less clear whether EBV contributes to the tumor phenotype in the two samples with lower read numbers where there is a lack of pronounced oncogenic latentgene expression.…”

“…The expression of the highly immunogenic EBNA2 gene in this case further supports the suspicion of immunosuppression. Despite this possibility, it seems likely that EBV latency genes contribute to tumor progression (23)(24)(25)(26) in this patient. Whether HHV-6B plays a role in tumor progression or whether expression is just a bystander effect of possible immunosuppression is unclear and will require further investigation.…”

Epigenetic silencing of tumor suppressor genes during in vitro Epstein–Barr virus infection

“…As seen in most human cancers, including EBVassociated cancers (14), our results also showed deregulation of tumor suppressors and cell-cycle checkpoints at both G1/S and G2/M transitions, namely Rb1/E2F1 and TP53/MDM2 arms, through alteration of CpG methylation. We and others have previously shown that EBV infection and expression of a number of viral latent proteins can specifically target these two important tumor-suppressor arms through multiple mechanisms (24,(26)(27)(28). We now provide further clues that demonstrate additional molecular mechanisms, which regulate TSG expression and therefore contribute to subsequent B-cell transformation.…”

Modulation of Enhancer Looping and Differential Gene Targeting by Epstein-Barr Virus Transcription Factors Directs Cellular Reprogramming

“…This residue is subsequently dephosphorylated by the CDC25 phosphatase at the end of G2, triggering entry into mitosis. EBV infection results in the deregulation of the cell-cycle, with EBNA 3C playing a key role in overriding G1/S, G2/M and mitotic checkpoints through numerous potential mechanisms that include transcriptional repression and the regulation of protein stability [83]–[84]. Disruption of the G2/M checkpoint may be mediated through effects on the Chk2 kinase and we have recently described upregulation of an activator of CDK1, RGC-32, in EBV-infected cells [69], [85].…”