NEW YORK (Reuters Health) - Epstein-Barr virus (EBV) alters the epigenetic landscape of host cells in a way that facilitates the development of gastric adenocarcinoma, researchers report. "We don't have data yet, but upregulated tumor-related genes or epigenomic aberrations might be targeted in novel therapy," Dr. Atsushi Kaneda of Graduate School of Medicine, Chiba University, in Japan, told Reuters Health by email. Previous studies have shown that EBV-positive gastric cancer has hallmark epigenetic and genetic features, including genome-wide DNA hypermethylation, PIK3CA mutations and genomic amplification of the PD-L1/L2 immune-checkpoint molecules. More recently, three-dimensional chromatin organization has been shown to play important roles in regulating gene expression, and aberrant chromatin topologies have been observed in cancer, Dr. Kaneda and colleagues note in Nature Genetics. The team investigated whether EBV-positive gastric cancer is associated with distinct 3D chromatin topologies and how that might contribute to EBV oncogenesis. In three EBV-positive gastric-cancer cell lines, there was a shared and conserved chromatin interaction, with increased DNA-methylation levels around gene transcription start sites that were consistent with these regions displaying epigenetic repression. The entire EBV genome appeared to be necessary to induce chromatin alterations and cross-species interactions at these EBV-interacting regions (EBVIRs) of the host genome. These epigenomic interactions unleashed latent enhancers to engage and activate nearby gastric cancer-related genes, a phenomenon the researchers called "enhancer infestation." One particular gene upregulated after EBV infection, H3K4me3, might prove to be a useful therapeutic target, the researchers say. "Our enhancer infestation model provides a novel mechanism of epigenetic tumorigenesis without requiring genomic structural alterations, by reprograming repressed heterochromatin through virus-host genomic interactions, which results in latent unused enhancers in heterochromatin being converted from silenced to active states and the upregulation of nearby tumor-related genes," they conclude. "We hope 'enhancer infestation' by EBV may help understand other cancers caused by EBV or other viruses, or caused by aberrant epigenomic alterations," Dr. Kaneda said. Source
