title: Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.
abstract: Epstein-Barr virus (EBV) is a well-known human herpesvirus associated with virtually all nasopharyngeal carcinoma (NPC) and approximately 10% of gastric cancer (GC) worldwide. Increasing evidence shows that acquired genetic and epigenetic alterations lead to the initiation and progression of NPC and GC. However, even deep whole exome sequencing studies showed a relatively low frequency of gene mutations in NPC and EBV-associated GC (EBVaGC), suggesting a predominant role of epigenetic abnormities, especially promoter CpG methylation, in the pathogenesis of NPC and EBVaGC. High frequencies of promoter methylation of tumor suppressor genes (TSGs) have been frequently reported in NPC and EBVaGC, with several EBV-induced methylated TSGs identified. Further characterization of the epigenomes (genome-wide CpG methylation profile--methylome) of NPC and EBVaGC shows that these EBV-associated tumors display a unique high CpG methylation epigenotype with more extensive gene methylation accumulation, indicating that EBV acts as a direct epigenetic driver for these cancers. Mechanistically, oncogenic modulation of cellular CpG methylation machinery, such as DNA methyltransferases (DNMTs), by EBV-encoded viral proteins accounts for the EBV-induced high CpG methylation epigenotype in NPC and EBVaGC. Thus, uncovering the EBV-associated unique epigenotype of NPC and EBVaGC would provide new insight into the molecular pathogenesis of these unique EBV-associated tumors and further help to develop pharmacologic strategies targeting cellular methylation machinery in these malignancies.
authors.affiliation: Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, Hong Kong SAR, China. qtao@cuhk.edu.hk.
authors.forename: Lili
authors.initials: L
authors.lastname: Li
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Guo
authors.forename: Francis K L
authors.initials: FK
authors.lastname: Chan
authors.forename: Qian
authors.initials: Q
authors.lastname: Tao
mesh_terms: D002277:Carcinoma; D018899:CpG Islands; D019175:DNA Methylation; D057890:Epigenomics; D004847:Epithelial Cells; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D008745:Methylation; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms; D014764:Viral Proteins
chemical_list: D014764:Viral Proteins