期刊
CANCERS
卷 10, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/cancers10040119
关键词
Epstein-Barr virus; NF-kappa B; EBNA1
类别
资金
- Research Grants Council of the Hong Kong SAR [17154516, C7027-16G]
- Health and Medical Research Fund [14131032]
- Areas of Excellence Scheme of the University Grants Committee [AoE/M-06/08]
- Cross Trait Joint Funds of the National Natural Science Foundation of China [U1405221]
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is one of the few viral proteins expressed by EBV in nasopharyngeal carcinoma (NPC), most likely because of its essential role in maintaining the viral genome in EBV-infected cells. In NPC, EBNA1 expression is driven by the BamHI-Q promoter (Qp), which is regulated by both cellular and viral factors. We previously determined that the expression of another group of EBV transcripts, BamHI-A rightward transcripts (BARTs), is associated with constitutively activated nuclear factor-kappa B (NF-kappa B) signaling in NPC cells. Here, we show that, like the EBV BART promoter, the EBV Qp also responds to NF-kappa B signaling. NF-kappa B p65, but not p50, can activate Qp in vitro, and NF-kappa B signaling regulates Qp-EBNA1 expression in NPC cells, as well as in other EBV-infected epithelial cells. The introduction of mutations in the putative NF-kappa B site reduced Qp activation by the NF-kappa B p65 subunit. Binding of p65 to Qp was shown by chromatin immunoprecipitation (ChIP) analysis, while electrophoretic mobility shift assays (EMSAs) demonstrated that p50 can also bind to Qp. Inhibition of NF-kappa B signaling by the I kappa B kinase inhibitor PS-1145 resulted in the downregulation of Qp-EBNA1 expression in C666-1 NPC cells. Since EBNA1 has been reported to block p65 activation by inhibiting IKKc/0 through an unknown mechanism, we suggest that, in NPC, NF-KB signaling and EBNA1 may form a regulatory loop which supports EBV latent gene expression, while also limiting NF-kappa B activity. These findings emphasize the role of NF-kappa B signaling in the regulation of EBV latency in EBV-associated tumors.
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