Division of Virology, Aichi Cancer Center Research Institute, Nagoya, Japan; Department of Virology, Nagoya University School of Medicine, Nagoya, Japan.
Rev Med Virol. 2014 May;24(3):142-53. doi: 10.1002/rmv.1780. Epub 2013 Dec 11.
The EBV is a human gamma-herpesvirus that is associated with a variety of neoplasms. Upon primary infection, it transiently runs a short lytic program and then predominantly establishes latent infection. Only a small percentage of infected cells switch from the latent stage into the lytic cycle and produce progeny viruses. Although EBV in cancer cells is mostly in the latent state, the lytic cycle of the virus is also expected to play a pivotal role in development and maintenance of tumors because of its association with secretion of cytokines or growth factors. Moreover, if efficient artificial induction of lytic replication could somehow be achieved, development of oncolytic therapy for EBV-positive cancers would be conceivable. Thus, understanding the switching mechanism is of essential importance. Reactivation of the virus from latency is dependent on expression of the viral BZLF1 protein. The BZLF1 promoter (Zp) normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate, calcium ionophore, or histone deacetylase inhibitors. Transcription from the Zp is regulated by the balance between active and suppressive epigenetic histone marks, including histone acetylation, histone H3 Lysine 4 trimethylation and histone H3 lysine 27 trimethylation, being mediated by multiple transcription factors, such as myocyte enhancer factor 2, specificity protein 1, and zinc finger E-box binding homeobox. This review will focus on such molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of the switching for oncogenesis.
EBV 是一种人类γ疱疹病毒，与多种肿瘤有关。初次感染时，它会短暂地进行短暂的裂解程序，然后主要建立潜伏感染。只有一小部分感染细胞从潜伏阶段转变为裂解周期并产生后代病毒。尽管癌细胞中的 EBV 大多处于潜伏状态，但由于病毒与细胞因子或生长因子的分泌有关，其裂解周期预计也将在肿瘤的发展和维持中发挥关键作用。此外，如果能够以某种方式有效地诱导裂解复制，那么针对 EBV 阳性癌症的溶瘤治疗的发展将是可以想象的。因此，了解切换机制至关重要。病毒从潜伏状态中重新激活依赖于病毒 BZLF1 蛋白的表达。BZLF1 启动子（Zp）通常仅表现出低基础活性，但在化学或生物诱导剂（如 12-O-十四烷酰佛波醇-13-乙酸酯、钙离子载体或组蛋白去乙酰化酶抑制剂）的作用下被激活。Zp 的转录受活跃和抑制性表观遗传组蛋白标记之间的平衡调节，包括组蛋白乙酰化、组蛋白 H3 赖氨酸 4 三甲基化和组蛋白 H3 赖氨酸 27 三甲基化，由多种转录因子（如肌细胞增强因子 2、特异性蛋白 1 和锌指 E-框结合同源盒）介导。本综述将重点介绍 EBV 裂解开关受控制的此类分子机制，并讨论开关对致癌作用的生理意义。
