A histone deacetylase inhibitor enhances recombinant adeno-associated virus-mediated gene expression in tumor cells.
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 confirmed in vivo. The use of this HDAC inhibitor may enhance the utility of rAAV-mediated transduction strategies for cancer gene therapy.
Okada
Takashi
T
Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, 3311-1 Yakushiji, Minami-Kawachi, Tochigi 329-0498, Japan. tokada@jichi.ac.jp
Uchibori
Ryosuke
R
Iwata-Okada
Mayumi
M
Takahashi
Masafumi
M
Nomoto
Tatsuya
T
Nonaka-Sarukawa
Mutsuko
M
Ito
Takayuki
T
Liu
Yuhe
Y
Mizukami
Hiroaki
H
Kume
Akihiro
A
Kobayashi
Eiji
E
Ozawa
Keiya
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D000229:Dependovirus / Q000235:genetics*; D047630:Depsipeptides / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D005822:Genetic Vectors; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D051381:Rats; D014161:Transduction, Genetic; D019076:Transgenes / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; C087123:romidepsin