Epstein-Barr virus lncBARTs induce IKZF3/Aiolos to promote oncogenesis in nasopharyngeal carcinoma

Epstein-Barr virus (EBV) latent infection is ubiquitously associated with nasopharyngeal carcinoma (NPC), expressing few viral proteins but abundant levels of viral noncoding RNAs (EBERs, miR-BARTs and lncBARTs) in nucleus. We previously showed that IKZF3/Aiolos is a downstream target of lncBARTs in EBV infected epithelial cells. However, little is known whether lncBARTs induce Aiolos for EBV latency and promote oncogenesis of EBV in NPC. Here we employed complex of technologies to explore the role of lncBARTs induced Aiolos in NPC. CRISPR Cas9-based analysis demonstrated that upregulation of Aiolos was associated with EBV infection and modulated by lncBARTs rather than miR-BARTs and EBNA1 in NPC cells. We found that Aiolos recruited H3K27 deacetylation to epigenetically silence expression of BZLF1 for maintaining EBV latency in NPC cells. Importantly, our study showed that Aiolos inhibited expression of a tumor suppressor LRIG1 to upregulate expression and phosphorylation of the growth receptor tyrosine kinase erbB2 for promoting NPC tumorigenesis in vitro and in vivo. Mice experiments further showed that Aiolos/BZLF1 axis is important for maintains EBV latency in vivo. In summary, this study revealed that EBV expressed lncBARTs plays critical role in the EBV latency and oncogenesis through upregulation of Aiolos pathway, which may be a potential target for treatment of NPC.