Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers

摘要: Epiregulin (EREG) induces cell growth by binding to the epidermal factor receptor (EGFR). Expression of EREG affects sensitivity cetuximab a chimeric monoclonal antibody that inhibits EGFR signaling pathway. The mechanism through which is regulated largely unknown, but methyl-array study previously performed our group revealed methylated in gastric cancer cells. In this study, we found gene expression was low 7 out 11 cells and downregulation mediated aberrant CpG methylation promoter. Treatment with 5-aza-CdR restored demethylated sites Compared DNA methyltransferase 1 (DNMT1), knock-down 3b (DNMT3b) significantly increased led demethylation specific promoter, suggesting DNMT3b primarily regulates silencing gene. observed 30% (4/13) human primary tumor tissues evaluated. addition methylation, results from chromatin immunoprecipitation assay demonstrated transcriptional levels were associated enrichment active histone marks (H3K4me3 AcH3) repressive mark (H3K27me2). dynamically occupancy H3K4me3 AcH3, while decreasing high H3K27me2, indicating dynamic modifications contribute regulation methylation. Finally, combination exerted synergistic anti-proliferative effect on Taken together, showed for first time epigenetically silenced modification.