Epstein-Barr virus latent membrane protein 2A upregulates UDP-glucose dehydrogenase gene expression via ERK and PI3K/Akt pathway

The Epstein-Barr virus latent membrane protein 2A (LMP2A) is frequently detected in nasopharyngeal carcinoma (NPC), a tumour of high metastatic capacity. A recent microarray assay notes that expression of the UDP-glucose dehydrogenase (UGDH) gene, participating in glycosaminoglycan synthesis, shows high correlation with LMP2A levels in NPC biopsies. This study extends the finding and demonstrates that the UGDH transcript and protein quantities, the enzyme activity, and glycosaminoglycan contents increase in LMP2A overexpressed human embryonic kidney 293 (HEK293) cells. The luciferase reporter gene assay demarcates that a region from 630 to 486bp upstream of the transcription start is critical for LMP2A-mediated gene expression. Moreover, a specificity protein 1 (Sp1) binding site mutation in this region reduces the LMP2A-responsive expression of the UGDH gene. Consistent with these findings, cell motility enhancement by LMP2A diminishes by treating the cells with Sp1-specific inhibitor and small interference RNA (siRNA). Using a signalling pathway-specific inhibitor, it is revealed that phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK), not c-Jun N-terminal kinase (JNK) and p38, participate in LMP2A-induced UGDH expression. This study provides a model for molecular mechanism participating in LMP2A-mediated UGDH gene activation.