Epigenetic Regulation of MAP3K8 in EBV-Associated Gastric Carcinoma

Super-enhancers (SEs) regulate gene expressions, which are critical for cell type-identity and tumorigenesis. Although genome wide H3K27ac profiling have revealed the presence of SE-associated genes in gastric cancer (GC), their roles remain unclear. In this study, ChIP-seq and HiChIP-seq experiments revealed mitogen-activated protein kinase 8 () to be an SE-associated gene with chromosome interactions in Epstein-Barr virus-associated gastric carcinoma (EBVaGC) cells. CRISPRi mediated repression of the SEs attenuated expression and EBVaGC cell proliferation. The results were validated by treating EBVaGC cells with bromodomain and the extra-terminal motif (BET) inhibitor, OTX015. Further, functional analysis of in EBVaGC revealed that silencing could inhibit the cell proliferation, colony formation, and migration of EBVaGC cells. RNA-seq and pathway analysis indicated that knocking down obstructed the notch signaling pathway and epithelial-mesenchymal transition (EMT) in EBVaGC cells. Further, analysis of the cancer genome atlas (TCGA) and GSE51575 databases exhibited augmented expression in gastric cancer and it was found to be inversely correlated with the disease-free progression of GC. Moreover, Spearman's correlation revealed that expression was positively correlated with the expressions of notch pathway and EMT related genes, such as, C-terminal binding protein 2 (), alpha smooth muscle actin isotype 2 (), transforming growth factor beta receptor 1 (), and snail family transcriptional repressors 1/2 (/) in GC. Taken together, we are the first to functionally interrogate the mechanism of SE-mediated regulation of in EBVaGC cell lines.