A histone deacetylase inhibitor enhances recombinant adeno-associated virus-mediated gene expression in tumor cells.
A histone deacetylase inhibitor enhances recombinant adeno-associated virus-mediated gene expression in tumor cells.
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DOI：
10.1016/j.ymthe.2005.11.010
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发表时间：
2006-04
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影响因子：
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通讯作者：
T. Okada;Ryosuke Uchibori;Mayumi Iwata-Okada;Masafumi Takahashi;T. Nomoto;M. Nonaka-Sarukawa;Takayuki Ito;Yuhe Liu;H. Mizukami;A. Kume;E. Kobayashi;K. Ozawa
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文献类型：
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作者：
T. Okada;Ryosuke Uchibori;Mayumi Iwata-Okada;Masafumi Takahashi;T. Nomoto;M. Nonaka-Sarukawa;Takayuki Ito;Yuhe Liu;H. Mizukami;A. Kume;E. Kobayashi;K. Ozawa
使用重组腺相关病毒（rAAV）转导癌细胞的效率较低，这限制了其在癌症基因治疗中的应用。我们以前曾试图通过施加DNA损伤应力来增强rAAV介导的癌细胞转导。在这项研究中，我们研究了组蛋白去乙酰化酶抑制剂FR 901228对rAAV 2型和5型介导的肿瘤转导的影响。FR 901228处理显著改善了四种癌细胞系中转基因的表达。细胞表面α v整联蛋白、FGF-R1和PDGF-R的水平通过FR 901228的存在适度增强。这些结果表明，HDAC抑制剂诱导的上级转导是由于转基因表达的增强而不是病毒进入的增加。此外，我们的特点是在附加型AAV载体基因组中的乙酰化组蛋白H3的协会通过使用染色质免疫沉淀试验。结果表明，上级转导可能与转导细胞中rAAV串联体的组蛋白相关染色质形式有关。在皮下肿瘤模型的分析中，体内证实了转基因表达的强烈增强以及治疗效果。这种HDAC抑制剂的使用可以增强rAAV介导的转导策略用于癌症基因治疗的效用。
The transduction of cancer cells using recombinant adeno-associated virus (rAAV) occurs with low efficiency, which limits its utility in cancer gene therapy. We have previously sought to enhance rAAV-mediated transduction of cancer cells by applying DNA-damaging stresses. In this study, we examined the effects of the histone deacetylase inhibitor FR901228 on tumor transduction mediated by rAAV types 2 and 5. FR901228 treatment significantly improved the expression of the transgene in four cancer cell lines. The cell surface levels of alpha v integrin, FGF-R1, and PDGF-R were modestly enhanced by the presence of FR901228. These results suggest that the superior transduction induced by the HDAC inhibitor was due to an enhancement of transgene expression rather than increased viral entry. Furthermore, we characterized the association of the acetylated histone H3 in the episomal AAV vector genome by using the chromatin immunoprecipitation assay. The results suggest that the superior transduction may be related to the proposed histone-associated chromatin form of the rAAV concatemer in transduced cells. In the analysis with subcutaneous tumor models, strong enhancement of the transgene expression as well as therapeutic effect was confirmedin vivo. The use of this HDAC inhibitor may enhance the utility of rAAV-mediated transduction strategies for cancer gene therapy.