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Published on: September 15, 2010
Enhanced adenovirus transgene expression in malignant cells treated with the histone deacetylase inhibitor FR901228
M Kitazono1, M E Goldsmith, T Aikou
1Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Abstract:
The presence of coxsackie and adenovirus receptor (CAR) and alpha(v) integrin on cell surfaces is required for efficient adenovirus infection. Treatment of cells with the histone deacetylase inhibitor FR901228 (depsipeptide) increased CAR and alpha(v) integrin RNA levels in six cancer cell lines. Sodium butyrate and trichostatin A, other histone deacetylase inhibitors, caused similar increases. Cells treated with FR901228 prior to infection had a 4-10-fold increase in transgene expression from a beta-galactosidase-expressing adenoviral vector. These studies suggest that FR901228 increases the efficiency of adenoviral transgene expression and may be useful in cancer gene therapy.
Insights
Histone deacetylase inhibitors like FR901228 enhance adenovirus infection by increasing cell surface receptors. This boosts adenoviral transgene expression, showing potential for cancer gene therapy.
Area of Science:
- Molecular Biology
- Virology
- Cancer Research
Background:
- Adenovirus infection efficiency depends on cell surface receptors: coxsackie and adenovirus receptor (CAR) and alpha(v) integrin.
- Histone deacetylase (HDAC) inhibitors are known to modulate gene expression.
Purpose of the Study:
- To investigate the effect of HDAC inhibitors on CAR and alpha(v) integrin expression.
- To determine if HDAC inhibition can enhance adenoviral transgene expression for potential cancer gene therapy applications.
Main Methods:
- Treatment of six cancer cell lines with the HDAC inhibitor FR901228 (depsipeptide).
- Analysis of CAR and alpha(v) integrin RNA levels following FR901228 treatment.
- Adenoviral infection with a beta-galactosidase-expressing vector in FR901228-treated cells to measure transgene expression.
Main Results:
- FR901228 treatment significantly increased CAR and alpha(v) integrin RNA levels in cancer cell lines.
- Other HDAC inhibitors, sodium butyrate and trichostatin A, produced similar increases in receptor expression.
- Pre-treatment with FR901228 resulted in a 4-10 fold increase in adenoviral transgene expression.
Conclusions:
- FR901228 effectively upregulates CAR and alpha(v) integrin, enhancing adenovirus cellular entry.
- HDAC inhibition represents a promising strategy to improve adenoviral vector efficiency.
- This approach holds potential for advancing cancer gene therapy by optimizing adenoviral transgene delivery.
