Abstract
EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.
Highlights
Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and the third leading cause of cancer-related death with an estimated 783,000 deaths in 2018 [1]
Epstein-Barr virus (EBV), one of the human gamma-herpesviruses, is a well-defined viral agent that strongly associates with malignancies of lymphoid and epithelial origin
EBVassociated gastric carcinoma (EBVaGC) is the most common malignancy caused by EBV infection
Summary
Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide and the third leading cause of cancer-related death with an estimated 783,000 deaths in 2018 [1]. EBVaGC has been shown to arise from monoclonal amplification of EBV-infected gastric cells, suggesting that viral infection is the early step of carcinogenesis [8,9]. Studies with infectious mononucleosis patients have suggested that the earliest event following primary infection is the expression of lytic genes. EBV switches to a latent phase, during which the viral genome remains as an episome largely quiescent in memory B cells with expression of certain viral miRNAs and latent proteins (reviewed in [11]). The lytic switch from latency is initiated with the expression of immediate early lytic genes, Zta and Rta, which transactivate themselves and early lytic genes, leading to viral DNA amplification [12,13,14]. Late lytic genes encoding glycoproteins as well as tegument and capsid proteins are expressed, and new viral particles are formed [15,16]
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