Xu Huanzhou, Koganti Siva, Li Chenglong, McIntosh Michael T, Bhaduri-McIntosh Sumita
Division of Infectious Diseases, Department of Pediatrics, University of Florida, Gainesville, Florida, United States of America.
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America.
PLoS Pathog. 2025 May 12;21(5):e1013166. doi: 10.1371/journal.ppat.1013166. eCollection 2025 May.
Epstein-Barr virus (EBV), a common gamma-herpesvirus linked to various malignancies, exploits host cellular mechanisms to promote oncogenesis. Our previous research identified the zinc finger protein ZC3H18 as a novel component of the cellular DNA replication machinery in the context of EBV-driven tumorigenesis. We now demonstrate that ZC3H18 expression is upregulated in EBV-transformed and cancer cell lines, as well as in EBV-positive diffuse large B-cell lymphomas from AIDS patients, compared to their EBV-negative counterparts, supporting its activation by EBV. Our experiments show that ZC3H18 expression is regulated by the key oncogenic factors STAT3 and MYC, as well as the essential viral protein EBNA1. Using inhibitors and genetic knockdown, we find that suppressing STAT3, MYC, or EBNA1 leads to decreased ZC3H18 levels, reduced cell viability, and increased apoptosis in EBV-positive B lymphoma cells. Furthermore, ZC3H18, STAT3, MYC, and EBNA1 mutually support each other's expression through a complex transcriptional network. Notably also, ZC3H18 transcriptionally enhances components of the NF-κB pathway, contributing to NF-κB signaling even in the absence of the EBV oncoprotein LMP1, which is crucial for cell proliferation and survival of several EBV-associated malignancies. Our findings reveal a novel regulatory axis in EBV-positive cancer cells involving STAT3, MYC, EBNA1, & ZC3H18, also linking ZC3H18 to the NF-κB pathway independently of LMP1. The involvement of EBNA1 in this network may explain, at least in part, the preferential upregulation of ZC3H18 in EBV-associated tumors and highlights predictive and therapeutic possibilities for such cancers.
爱泼斯坦-巴尔病毒（EBV）是一种常见的γ-疱疹病毒，与多种恶性肿瘤相关，它利用宿主细胞机制促进肿瘤发生。我们之前的研究确定锌指蛋白ZC3H18是EBV驱动肿瘤发生过程中细胞DNA复制机制的一个新成分。我们现在证明，与EBV阴性的对应细胞相比，ZC3H18在EBV转化的细胞系和癌细胞系以及艾滋病患者的EBV阳性弥漫性大B细胞淋巴瘤中表达上调，这支持了EBV对其的激活作用。我们的实验表明，ZC3H18的表达受关键致癌因子STAT3和MYC以及重要病毒蛋白EBNA1的调控。使用抑制剂和基因敲低技术，我们发现抑制STAT3、MYC或EBNA1会导致EBV阳性B淋巴瘤细胞中ZC3H18水平降低、细胞活力下降和凋亡增加。此外，ZC3H18、STAT3、MYC和EBNA1通过一个复杂的转录网络相互支持彼此的表达。同样值得注意的是，ZC3H18在转录水平上增强NF-κB途径的成分，即使在没有对几种EBV相关恶性肿瘤的细胞增殖和存活至关重要的EBV癌蛋白LMP1的情况下，也能促进NF-κB信号传导。我们的研究结果揭示了EBV阳性癌细胞中一个涉及STAT3、MYC、EBNA1和ZC3H18的新调控轴，还将ZC3H18独立于LMP1与NF-κB途径联系起来。EBNA1参与这个网络可能至少部分解释了ZC3H18在EBV相关肿瘤中的优先上调，并突出了此类癌症的预测和治疗可能性。
