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Viruses 2013, 5(10), 2561-2572; doi:10.3390/v5102561

Inhibition of Histone Deacetylation and DNA Methylation Improves Gene Expression Mediated by the Adeno-Associated Virus/Phage in Cancer Cells

1
Phage Therapy Group, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
2
Epigenetic Group, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
*
Author to whom correspondence should be addressed.
Received: 3 September 2013 / Revised: 14 October 2013 / Accepted: 15 October 2013 / Published: 22 October 2013
(This article belongs to the Section Bacterial Viruses)
View Full-Text   |   Download PDF [587 KB, 12 May 2015; original version 12 May 2015]   |  

Abstract

Bacteriophage (phage), viruses that infect bacteria only, have become promising vectors for targeted systemic delivery of genes to cancer, although, with poor efficiency. We previously designed an improved phage vector by incorporating cis genetic elements of adeno-associated virus (AAV). This novel AAV/phage hybrid (AAVP) specifically targeted systemic delivery of therapeutic genes into tumors. To advance the AAVP vector, we recently introduced the stress-inducible Grp78 tumor specific promoter and found that this dual tumor-targeted AAVP provides persistent gene expression, over time, in cancer cells compared to silenced gene expression from the CMV promoter in the parental AAVP. Herein, we investigated the effect of histone deacetylation and DNA methylation on AAVP-mediated gene expression in cancer cells and explored the effect of cell confluence state on AAVP gene expression efficacy. Using a combination of AAVP expressing the GFP reporter gene, flow cytometry, inhibitors of histone deacetylation, and DNA methylation, we have demonstrated that histone deacetylation and DNA methylation are associated with silencing of gene expression from the CMV promoter in the parental AAVP. Importantly, inhibitors of histone deacetylases boost gene expression in cancer cells from the Grp78 promoter in the dual tumor-targeted AAVP. However, cell confluence had no effect on AAVP-guided gene expression. Our findings prove that combination of histone deacetylase inhibitor drugs with the Grp78 promoter is an effective approach to improve AAVP-mediated gene expression in cancer cells and should be considered for AAVP-based clinical cancer gene therapy. View Full-Text
Keywords: bacteriophage; phage-targeted gene transfer; cancer gene therapy; AAV/phage; Grp78; histone acetylation/deacetylation; DNA methylation bacteriophage; phage-targeted gene transfer; cancer gene therapy; AAV/phage; Grp78; histone acetylation/deacetylation; DNA methylation
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Kia, A.; Yata, T.; Hajji, N.; Hajitou, A. Inhibition of Histone Deacetylation and DNA Methylation Improves Gene Expression Mediated by the Adeno-Associated Virus/Phage in Cancer Cells. Viruses 2013, 5, 2561-2572.

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