Impact of novel histone deacetylase inhibitors, CHAP31 and FR901228 (FK228), on adenovirus-mediated transgene expression.
BACKGROUND
Histone deacetylase inhibitors (HDIs) are known to enhance adenovirus (Ad)-mediated transgene expression. Recently, novel HDIs, including cyclic hydroxamic-acid-containing peptide 31 (CHAP31) and FR901228 (FK228), have been developed.


METHODS
The effects of these two novel HDIs on Ad-transduced or endogenous gene expression were investigated. Acetylation of core histones and the expression of the coxsackie and adenovirus receptor (CAR) in HDI-treated cells were examined using Western blot and a quantitative reverse transcription polymerase chain reaction (TaqMan RT-PCR), respectively. Their in vivo effect on adenoviral gene expression was investigated in BALB/c mice.


RESULTS
Both compounds enhanced and prolonged Ad-mediated beta-galactosidase expression more effectively than did trichostatin A, a classic HDI. The same effect was observed in Ad-transduced heat shock protein 72 (HSP72), but not in hyperthermia-induced endogenous expression of HSP72, suggesting that the effect is specific for transduced gene expression. Hyperacetylation of core histones induced by HDIs was considered responsible for the augmentative effects of gene expression. Intravenous administration of either CHAP31 or FR901228 enhanced beta-galactosidase expression in mice infected with AdLacZ.


CONCLUSIONS
CHAP31 and FR901228 amplified Ad-mediated transgene expression. The enhancement of transgene expression by HDIs may result in fewer vector doses for necessary gene expression, helping to alleviate disadvantages caused by Ad vectors. This could be a useful tool in overcoming current limitations of gene therapy using adenovirus vectors.
Taura
Kojiro
K
Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Yamamoto
Yuzo
Y
Nakajima
Akio
A
Hata
Koichiro
K
Uchinami
Hiroshi
H
Yonezawa
Kei
K
Hatano
Etsuro
E
Nishino
Norikazu
N
Yamaoka
Yoshio
Y
D000107:Acetylation; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002478:Cells, Cultured; D047630:Depsipeptides / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D018014:Gene Transfer Techniques; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011991:Receptors, Virus / Q000096:biosynthesis; D014158:Transcription, Genetic; D019076:Transgenes / Q000187:drug effects*; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics
D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D010456:Peptides, Cyclic; D011991:Receptors, Virus; C505396:cyclic hydroxamic acid-containing peptide 31; C087123:romidepsin; D001616:beta-Galactosidase