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.EB病毒（Epstein-Barr virus，EBV）可在人体内建立终身潜伏感染，并与多种淋巴上皮源性癌症相关。在鼻咽癌（nasopharyngeal carcinoma，NPC）中，EBV仅表达少量病毒蛋白，但BamHI-A向右转录本（BamHI-A rightwards transcript，BART）RNA水平显著升高，该转录本包含超过40种微小RNA以及一个长链非编码RNA（long non-coding RNAs，lncRNAs）家族。BART来源长链非编码RNA的表达调控可显著影响鼻咽癌细胞中与细胞黏附、氧化还原酶活性、炎症及免疫相关的基因表达。值得注意的是，在BART长链非编码RNA敲低后的鼻咽癌C666-1细胞中，IKZF3（Aiolos，在淋巴细胞发育与细胞黏附中发挥作用）以及KDM1B（参与基因组印记与启动子组蛋白去甲基化过程）的表达出现下调。由于Aiolos的正常表达仅局限于淋巴细胞，在上皮细胞中极少被检测到，研究人员通过在EBV阳性与阴性上皮细胞中过表达主要的BART长链非编码RNA异构体RPMS1，验证了BART长链非编码RNA可诱导Aiolos的表达。在EBV感染的鼻咽癌细胞的细胞核中，BART长链非编码RNA可与CBP/p300复合物、RNA聚合酶II（Pol II）以及Brd4相结合。经JQ1型BET溴结构域抑制剂处理后，BART长链非编码RNA在细胞核内的调控功能会被破坏。上述数据表明，BART长链非编码RNA可能通过与染色质重塑及超级增强子调控机器相互作用，在EBV相关肿瘤中介导表观遗传调控。EBV似乎通过限制其他潜伏病毒蛋白的表达以逃避免疫监视，同时借助BART长链非编码RNA调控宿主基因表达以维持病毒潜伏状态；而BART长链非编码RNA介导的宿主基因异常表达，最终可推动鼻咽癌发生与免疫逃逸。