Oncogenic induction of cellular high CpG methylation by Epstein-Barr virus in malignant epithelial cells.

Epstein-Barr virus (EBV) is a well-known human herpesvirus associated
with virtually all nasopharyngeal carcinoma (NPC) and ~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.

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