Inhibition of histone deacetylation and DNA methylation improves gene expression mediated by the adeno-associated virus/phage in cancer cells
Author(s)
Kia, A
Yata, T
Hajji, N
Hajitou, A
Type
Journal Article
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.
Date Issued
2013-10-22
Date Acceptance
2013-10-15
Citation
Viruses, 2013, 5 (10), pp.2561-2572
ISSN
1999-4915
Publisher
MDPI
Start Page
2561
End Page
2572
Journal / Book Title
Viruses
Volume
5
Issue
10
Copyright Statement
© 2013 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Medical Research Council (MRC)
Grant Number
G0701159
Subjects
Science & Technology
Life Sciences & Biomedicine
Virology
VIROLOGY
bacteriophage
phage-targeted gene transfer
cancer gene therapy
AAV/phage
Grp78
histone acetylation/deacetylation
DNA methylation
VIRALLY TRANSDUCED GENES
IMMEDIATE-EARLY PROMOTER
PHASE-II TRIAL
VORINOSTAT
DELIVERY
VASCULATURE
ACTIVATION
CONSORTIUM
GRP78/BIP
VECTORS
Acetylation
Animals
Bacteriophages
Cell Line, Tumor
DNA Methylation
DNA, Viral
Dependovirus
Flow Cytometry
Gene Expression Profiling
Gene Expression Regulation, Viral
Gene Silencing
Genes, Reporter
Green Fluorescent Proteins
Histones
Humans
Promoter Regions, Genetic
Protein Processing, Post-Translational
Rats
Recombination, Genetic
Publication Status
Published