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

Viruses

Azadeh Kia²  Teerapong Yata²  Nabil Hajji¹ 

[1] Epigenetic Group, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK; E-Mail:;Phage Therapy Group, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK; E-Mails:

关键词: bacteriophage;    phage-targeted gene transfer;    cancer gene therapy;    AAV/phage;    Grp78;    histone acetylation/deacetylation;    DNA methylation;   

DOI  :  10.3390/v5102561

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.