Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Cancer Gene Ther. 2010 Mar;17(3):203-11. doi: 10.1038/cgt.2009.65. Epub 2009 Oct 23.
The cytomegalovirus (CMV) promoter is considered to be one of the strongest promoters for driving the in vivo expression of genes encoded by DNA vaccines. However, the efficacy of DNA vaccines has so far been disappointing (particularly in humans), and this might be explained in part by histone deacetylase (HDAC)-mediated chromatin condensation. Hence, we sought to investigate whether increasing the expression of DNA vaccine antigens with the HDAC inhibitor OSU-HDAC42 would enhance the efficacy of DNA vaccines in vivo. A luciferase assay was used to determine the effects of OSU-HDAC42 on CMV promoter-driven DNA plasmids in vitro and in vivo. Three HDAC inhibitors were able to activate expression from the CMV promoter in NIH3T3 cells and MBT-2 bladder cancer cells. The expression of luciferase was significantly enhanced by co-administration of pCMV-luciferase and OSU-HDAC42 in mice. To explore whether OSU-HDAC42 could enhance the specific antitumor activity of a neu DNA vaccine driven by the CMV promoter, we evaluated therapeutic effects and immune responses in a mouse tumor natively overexpressing HER2/neu. Mice receiving OSU-HDAC42 in combination with the CMV-promoter neu DNA vaccine exhibited stronger antitumor effects than mice given the DNA vaccine only. In addition, a correlation between the antitumor effects and the specific cellular immune responses was observed in the mice receiving the DNA vaccine and OSU-HDAC42.
巨细胞病毒（CMV）启动子被认为是驱动 DNA 疫苗编码基因体内表达的最强启动子之一。然而，DNA 疫苗的疗效迄今为止一直令人失望（尤其是在人类中），这部分可以用组蛋白去乙酰化酶（HDAC）介导的染色质凝聚来解释。因此，我们试图研究是否可以通过 HDAC 抑制剂 OSU-HDAC42 增加 DNA 疫苗抗原的表达来提高 DNA 疫苗在体内的疗效。荧光素酶测定用于体外和体内确定 OSU-HDAC42 对 CMV 启动子驱动的 DNA 质粒的影响。三种 HDAC 抑制剂能够激活 NIH3T3 细胞和 MBT-2 膀胱癌细胞中 CMV 启动子的表达。在小鼠中，共给予 pCMV-荧光素酶和 OSU-HDAC42 可显著增强荧光素的表达。为了探讨 OSU-HDAC42 是否可以增强 CMV 启动子驱动的 neu DNA 疫苗的特异性抗肿瘤活性，我们在过表达 HER2/neu 的小鼠肿瘤中评估了治疗效果和免疫反应。与仅给予 DNA 疫苗的小鼠相比，接受 OSU-HDAC42 联合 CMV 启动子 neu DNA 疫苗的小鼠表现出更强的抗肿瘤作用。此外，在接受 DNA 疫苗和 OSU-HDAC42 的小鼠中观察到抗肿瘤作用与特定细胞免疫反应之间存在相关性。
