Amplification of transgene expression in vitro and in vivo using a novel inhibitor of histone deacetylase.
Enhancement of transgene expression is an important issue in human gene therapy. Here we describe a novel system for enhancing transgene expression by cointroduction of plasmid DNA with FR901228, a water-soluble histone deacetylase inhibitor. When a luciferase expression vector was cointroduced into cells with FR901228, luciferase gene expression was enhanced 50-fold in the mouse melanoma cell line B16-F1 and 5200-fold in NIH3T3 cells in comparison to cells without the drug. Luciferase gene expression enhancement was dependent on both drug dose and treatment time. Acetylated histones increased in accordance with drug dose, and the activation of gene expression occurred at the transcriptional level. The stimulation of luciferase gene expression by FR901228 was also observed in a B16-F1 clone stably expressing luciferase. Cointroduction of the luciferase plasmid with FR901228 into a B16-F1 tumor mass activated luciferase gene expression 3- to 4-fold. Thus, activation of transgene expression by FR901228 may serve as a new tool for gene therapy.
Yamano
T
T
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Suita, Japan.
Ura
K
K
Morishita
R
R
Nakajima
H
H
Monden
M
M
Kaneda
Y
Y
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D047630:Depsipeptides; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010456:Peptides, Cyclic; D014162:Transfection; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; C087123:romidepsin; D008156:Luciferases