title: Impact of novel histone deacetylase inhibitors, CHAP31 and FR901228 (FK228), on adenovirus-mediated transgene expression.
abstract: 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.
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Akio
authors.initials: A
authors.lastname: Nakajima
authors.forename: Koichiro
authors.initials: K
authors.lastname: Hata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Uchinami
authors.forename: Kei
authors.initials: K
authors.lastname: Yonezawa
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.forename: Norikazu
authors.initials: N
authors.lastname: Nishino
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamaoka
mesh_terms: 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
chemical_list: 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