Department of Otorhinolaryngology-Head and Neck Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Department of Microbiology, Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
J Virol. 2018 Aug 29;92(18). doi: 10.1128/JVI.00663-18. Print 2018 Sep 15.
Cell cycle regulation is one of the hallmarks of virus-mediated oncogenesis. Epstein-Barr virus (EBV)-induced lymphomas express a repertoire of essential viral latent proteins that regulate expression of cell cycle-related proteins to dysregulate this process, thereby facilitating the proliferation of infected cells. We now demonstrate that the essential EBV latent protein 3C (EBNA3C) stabilizes cyclin D2 to regulate cell cycle progression. More specifically, EBNA3C directly binds to cyclin D2 and they colocalize together in nuclear compartments. We show that EBNA3C regulates the promoter of cyclin D2 through cooperation with master transcription factor Bcl6 and enhances its stability by inhibiting its ubiquitin-dependent degradation. EBNA3C also promoted cell proliferation in the presence of cyclin D2, suggesting that cyclin D2 contributes to EBNA3C-mediated cell cycle progression. These results provide new clues as to the role of this essential viral latent protein and its ability to regulate expression of cellular factors, which drives the oncogenic process. Epstein-Barr virus (EBV) is the first identified human tumor virus and is associated with a range of human cancers. During EBV-induced lymphomas, the essential viral latent proteins modify the expression of cell cycle-related proteins to disturb the cell cycle process, thereby facilitating the proliferative process. The essential EBV nuclear antigen 3C (EBNA3C) plays an important role in EBV-mediated B-cell transformation. Here we show that EBNA3C stabilizes cyclin D2 to regulate cell cycle progression. More specifically, EBNA3C directly binds to cyclin D2, and they colocalize together in nuclear compartments. EBNA3C enhances cyclin D2 stability by inhibiting its ubiquitin-dependent degradation and significantly promotes cell proliferation in the presence of cyclin D2. Our results provide novel insights into the function of EBNA3C on cell progression by regulating the cyclin D2 protein and raise the possibility of the development of new anticancer therapies against EBV-associated cancers.
细胞周期调控是病毒介导致癌作用的标志之一。 Epstein-Barr 病毒（EBV）诱导的淋巴瘤表达一系列必需的病毒潜伏蛋白，这些蛋白调节细胞周期相关蛋白的表达，使该过程失调，从而促进受感染细胞的增殖。我们现在证明，必需的 EBV 潜伏蛋白 3C（EBNA3C）稳定细胞周期蛋白 D2 以调节细胞周期进程。更具体地说，EBNA3C 直接与细胞周期蛋白 D2 结合，并且它们在核区室中共定位。我们表明，EBNA3C 通过与主转录因子 Bcl6 合作调节细胞周期蛋白 D2 的启动子，并通过抑制其泛素依赖性降解来增强其稳定性。EBNA3C 还在存在细胞周期蛋白 D2 的情况下促进细胞增殖，表明细胞周期蛋白 D2 有助于 EBNA3C 介导的细胞周期进程。这些结果为这种必需的病毒潜伏蛋白的作用及其调节细胞因子表达的能力提供了新的线索，这推动了致癌过程。Epstein-Barr 病毒（EBV）是第一个被鉴定的人类肿瘤病毒，与多种人类癌症有关。在 EBV 诱导的淋巴瘤中，必需的病毒潜伏蛋白会改变细胞周期相关蛋白的表达，扰乱细胞周期过程，从而促进增殖过程。必需的 EBV 核抗原 3C（EBNA3C）在 EBV 介导的 B 细胞转化中起重要作用。在这里，我们表明 EBNA3C 通过稳定细胞周期蛋白 D2 来调节细胞周期进程。更具体地说，EBNA3C 直接与细胞周期蛋白 D2 结合，并且它们在核区室中共定位。EBNA3C 通过抑制其泛素依赖性降解来增强细胞周期蛋白 D2 的稳定性，并在存在细胞周期蛋白 D2 的情况下显著促进细胞增殖。我们的结果为 EBNA3C 通过调节细胞周期蛋白 D2 蛋白对细胞进展的功能提供了新的见解，并提出了针对 EBV 相关癌症开发新的抗癌疗法的可能性。
