Epstein-Barr virus BART-lncRNAs function as epigenetic modulators in nasopharyngeal carcinoma

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 only few viral proteins but elevated levels of BamHI-A rightwards transcript (BART) RNA, which includes more than 40 microRNAs and a family of long non-coding RNAs (lncRNAs). Modulation of BART-lncRNAs expression significantly affects expression of genes associated with cell adhesion, oxidoreductase activity, inflammation and immunity in NPC cells. Notably, downregulation of IKZF3 (Aiolos), which plays a role in lymphocyte development and cell attachment, and KDM1B, which is required for genomic imprinting and promoter histone demethylation, 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 epithelial cells. BARTlncRNA associated with the CBP/p300 complex RNA polymerase II (Pol II) and Brd4 in the nucleus of EBV-infected NPC cells. The regulatory function of BART-lncRNA in the nucleus is disrupted following JQ1 BET bromodomain inhibitor treatment. These data suggest that BART-lncRNAs may mediate epigenetic regulation through interaction with chromatin remodeling and super-enhancer regulation machinery in EBV associated tumors. EBV appears to restrict expression of other latent viral protein to evade immune response but utilize BART-lncRNAs to modulate gene expression to maintain virus latency, with aberrant expression of host genes mediated by BART lncRNA leading to NPC oncogenesis and immune evasion.