Abstract
Epstein-Barr virus (EBV) establishes lifelong latent infection in humans and is associated with several lymphoid and epithelial cancers. In nasopharyngeal carcinoma (NPC), EBV expresses few viral proteins but elevated levels of Bam-HI A rightward transcripts (BARTs) RNA, which includes viral microRNAs and long non-coding RNAs (lncRNAs). BART lncRNAs localize within the nucleus of EBV-infected cells and knockdown of BART lncRNAs significantly affects the expression of genes associated with cell adhesion, oxidoreductase activity, inflammation, and immunity. Notably, downregulation of IKAROS family zinc finger 3 (IKZF3/Aiolos), which plays a role in lymphocyte development and cell attachment, occurred in NPC C666-1 cells following BART lncRNA-knockdown. Since Aiolos expression is normally restricted to lymphoid cells and rarely observed in epithelial cells, induction of Aiolos by BART lncRNA was confirmed by expressing the major BART lncRNA isoform, RPMS1, in EBV-positive and -negative cells. BART lncRNA associated with the CBP/p300 complex and RNA polymerase II (Pol II) in the nucleus, suggesting that BART lncRNAs may mediate epigenetic regulation of gene expression through interaction with the chromatin remodeling machinery. This contention is further supported by evidence that BART lncRNA appears to stall Pol II at the promoter region and may regulate IFNB1 and CXCL8 expression by inhibiting transcription by Pol II in NPC. We hypothesize that EBV BART lncRNA expression modulates host gene expression and maintains EBV latency by interfering with histone methylation and acetylation processes. Aberrant expression of affected host genes mediated by BART lncRNA may lead to immune evasion, progression, and metastasis of NPC.
Highlights
Epstein-Barr virus (EBV) infects more than 95% of the human population
EBV expresses the highest levels of Bam-HI A rightward transcripts (BARTs) RPMS1 in C666-1, which is naturally infected with EBV, while relatively lower levels of RPMS1 are detected in HeLa-Bx1 and AGSBx1, which have been artificially infected with EBV in vitro, and in both latency I and III Mutu cell lines, which are derived from Burkitt’s lymphoma (Figure 1B)
To further examine our hypothesis that EBV BART long non-coding RNAs (lncRNAs) is involved in epigenetic regulation of gene expression, we explored a possible association between BART lncRNA and the CREB-binding protein (CBP), which interacts with various transcription factors
Summary
Epstein-Barr virus (EBV) infects more than 95% of the human population. Primary infection with EBV is usually asymptomatic, if infection first occurs in young adulthood, mononucleosis may develop [1]. EBV remains latent in memory B cells and is kept in check by a competent immune surveillance system which continuously removes EBVinfected cells in which EBV has become activated from its stringent latency program [2]. When the human immune system is compromised, latently EBV-infected cells may be transformed into lymphoblasts, which are characterized by increased cell proliferation, as seen in lymphoproliferative diseases. While latent infection of resting B cells with EBV and virus shedding from oral pharyngeal tissues normally cause no serious risk to the health of immunocompetent individuals, the presence of EBV can give rise to certain epithelial cancers, including nasopharyngeal carcinoma (NPC), when combined with genetic abnormalities or undefined environmental factors. We postulate that infection with activated EBV in nasopharyngeal epithelial cells predisposed toward establishment of viral latency may lead to the origin or development of NPC. How does EBV maintain latency in NPC cells without these viral functions? It is likely that the mechanism regulating the EBV latency program in NPC cells drives EBV oncogenesis
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