Abstract：
Metabolic reprogramming induced by Epstein-Barr virus (EBV) often mirrors metabolic changes observed in cancer cells. Accumulating evidence suggests that lytic reactivation is crucial in EBV-associated oncogenesis. The aim of this study was to explore the role of metabolite changes in EBV-associated malignancies and viral life cycle control. We first revealed that EBV (LMP1) accelerates the secretion of the oncometabolite D-2HG, and serum D-2HG level is a potential diagnostic biomarker for NPC. EBV (LMP1)-driven metabolite changes disrupts the homeostasis of global DNA methylation and demethylation, which have a significantly inhibitory effect on active DNA demethylation and 5hmC content. We found that loss of 5hmC indicates a poor prognosis for NPC patients, and that 5hmC modification is a restriction factor of EBV reactivation. We confirmed a novel EBV reactivation inhibitor, α-KG, which inhibits the expression of EBV lytic genes with CpG-containing ZREs and the latent-lytic switch by enhancing 5hmC modification. Our results demonstrate a novel mechanism of which metabolite abnormality driven by EBV controls the viral lytic reactivation through epigenetic modification. This study presents a potential strategy for blocking EBV reactivation, and provides potential targets for the diagnosis and therapy of NPC.
摘要：
由EB病毒(EBV)诱导的代谢重编程通常反映在癌细胞中观察到的代谢变化。越来越多的证据表明，裂解液的再激活在EBV相关的肿瘤发生中至关重要。这项研究的目的是探讨代谢物变化在EBV相关恶性肿瘤和病毒生命周期控制中的作用。我们首先揭示了EBV（LMP1）加速代谢产物D-2HG的分泌，血清D-2HG水平是NPC的潜在诊断生物标志物。EBV（LMP1）驱动的代谢物变化破坏了全局DNA甲基化和去甲基化的稳态，对活性DNA去甲基化和5hmC含量有明显的抑制作用。我们发现5hmC的丢失表明NPC患者的预后不良，5hmC修饰是EBV再激活的限制因素。我们证实了一种新的EBV再激活抑制剂，α-KG,通过增强5hmC修饰，抑制含有CpG的ZREs和潜伏裂解开关的EBV裂解基因的表达。我们的结果证明了由EBV驱动的代谢物异常通过表观遗传修饰控制病毒裂解再激活的新机制。这项研究提出了阻断EBV再激活的潜在策略，为鼻咽癌的诊断和治疗提供了潜在的靶点。
