The role of glucose metabolism reprogrammed by EBV infection in the pathogenesis of nasopharyngeal carcinoma

Abstract

Viruses infect host cells and alter the host’s cellular signaling to modulate cell proliferation and energy homeostasis to support viral infection. Unfortunately, some of these effects in infected cells also promote or facilitate carcinogenesis. Epstein-Barr virus (EBV) infection is closely related to nasopharyngeal carcinoma (NPC) and is present in almost 100% of undifferentiated NPC tissues. The role of EBV infection in NPC pathogenesis is poorly understood. Instead of undergoing the lytic infection in normal pharyngeal epithelium, EBV infection undergoes predominantly latent infection in NPC. The dynamic switch from EBV lytic infection in normal nasopharyngeal cells to latent infection in NPC may represent an important step in NPC pathogenesis. Recent studies showed that both B cells and epithelial cells infected with EBV are capable of enhancing glucose metabolism to maintain EBV persistence in latent infection, indicating that the reprogramming of glucose metabolism may have a significant role in EBV-associated carcinogenesis. The reprogramming of glucose metabolism is a common hallmark in human cancers, including NPC. The part played by EBV-modulated energy metabolism in NPC pathogenesis is poorly defined. Recently, the EBV-LMP1 has been reported to enhance glycolysis to promote cell transformation. Detail mechanisms remain to be elucidated. In this study, EBV infection was shown to reprogram glucose metabolism from oxidative phosphorylation to glycolysis using immortalized nasopharyngeal epithelial cell lines established in our laboratory. Its potential involvement in malignant transformation as well as cell motility were systematically investigated. RNA sequence analysis in 3 pairs of EBV-infected and uninfected immortalized nasopharyngeal epithelial cells revealed in common significant dyregulation of 253 genes. Biological process analysis of these 253 overlapped genes revealed that they are associated with glucose metabolism. Pathway enrichment analysis of these genes based on the KEGG database indicated their involvement in energy metabolism associated pathways including AMPK signaling and PI3K-AKT signaling. LMP1-enhanced glycolysis was shown to play a significant role in EBV-associated tumorigenesis by modulating multiple cellular behaviors. The EBV-encoded LMP1 activates mTORC1 signaling to modulate NF-κB activation, which further drives Glut-1 transcription to promote malignant transformation of immortalized nasopharyngeal epithelial cells. Interestingly, the LMP1 activation of mTORC2 signaling promotes the PDHE1α distribution into the nucleus, a process dependent on Ser293 phosphorylation of PDHE1α. The nuclear PDHE1α enhances histone H3K9 acetylation, and promotes H3K9Ac binding to the Snail promoter to drive cell mobility in nasopharyngeal epithelial cells. In summary, this study systematically examined the molecular mechanisms of EBV-encoded LMP1 in the reprogramming of glucose metabolism and its potential contributions to NPC malignancy. These findings also provide insights into how EBV infection may contribute to NPC pathogenesis through the alteration of host metabolic pathways, and may provide novel therapeutic targets for NPC treatment.