Figure 1. Model of oncogenic modulation of cellular CpG methylation machinery by Epstein-Barr virus (EBV) and EBV-induced high methylation epigenotype in malignant epithelial cells.

EBV-encoded proteins regulate multiple components of the cellular methylation machinery through either cellular signaling pathways or transcription complexes, which finally leads to tumor suppressor gene (TSG) methylation and silencing and contributes to nasopharyngeal carcinoma (NPC) and EBV-associated gastric cancer (EBVaGC) pathogenesis. EBNA1, EBV-associated nuclear antigen 1; LMP, latent membrane protein; JNK, c-Jun N-terminal kinase; STAT3, signal transducers and activators of transcription 3; PI3K/AKT, phosphatidylinositol 3-kinase (PI3K)/AKT; DNMT, DNA methyltransferase; HDAC, histone deacetylase; PcG, poly-comb group; ?, unknown mechanism.