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Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells

Cancer Gene Therapy volume 11, pages 477–486 (2004)Cite this article

Abstract

Studies on bladder cancer cell lines have shown that low adenoviral (Ad) infectivity is associated with low-level coxsackie adenovirus receptor (CAR) expression. Recently, we and others demonstrated a tumor stage- and grade-dependent downregulation of CAR expression in a large series of clinical bladder cancer specimens. Here, we demonstrate adenoviral gene transfer can be markedly enhanced in bladder cancer cells by upregulation of CAR through the use of certain differentiating agents, including the histone deacetylase inhibitors (HDACI) trichostatin A and sodium phenylbutyrate. CAR upregulation to supraphysiologic levels was demonstrated by quantitative rt-PCR, Western blotting, flow cytometry and adenoviral gene transfer. Normal urothelial cells and CAR-positive papilloma cells (RT4) failed to demonstrate upregulation under the same conditions. Upregulation was cell cycle dependent, associated with increased adenoviral gene transfer and persisted for at least 7 days after a single treatment. Such upregulation, however, appears to be tumor cell specific, as other CAR-negative cell lines failed to demonstrate enhanced adenoviral gene transfer with the same treatments. These results provide a rational basis for combining HDACI therapy with gene therapy as a method of augmenting activity in bladder cancer, but this strategy may not be universally applicable to other cell types.

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Acknowledgements

This work is supported by the Flight Attendant Medical Research Institute and in part by a research grant from the Max Kade foundation, New York, NY (to MDS).

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Author notes

  1. Markus D Sachs: These authors contributed equally to this work.

Authors and Affiliations

  1. Brady Urological Institute, Johns Hopkins Hospital, Marburg 205, 600 N. Wolfe Street, Baltimore, 21287-2101, Maryland, USA

    Markus D Sachs, Meera Ramamurthy, Meera Ramamurthy, Wasim Chowdhury, Ying Li, Mark P Schoenberg & Ronald Rodriguez

  2. Department of Urology, Charite Medical School, Humboldt University Berlin, Schumannstr. 20/21, Berlin, 10117, Germany

    Markus D Sachs

  3. The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Henk van der Poel & Winald Gerritsen

  4. GenVec, 65 West Watkins Mill, Gaithersburg, 20878, Maryland, USA

    Thomas J Wickham

  5. Gene Therapy Lab, Vrije-University, Amsterdam, The Netherlands

    Martine Lamfers & Winald Gerritsen

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Correspondence to Ronald Rodriguez.

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Sachs, M., Ramamurthy, M., Poel, H. et al. Histone deacetylase inhibitors upregulate expression of the coxsackie adenovirus receptor (CAR) preferentially in bladder cancer cells. Cancer Gene Ther 11, 477–486 (2004). https://doi.org/10.1038/sj.cgt.7700726

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