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Research Articles: Therapeutics, Targets, and Development

Modulation of topoisomerase II expression by a DNA sequence-specific polyamide

¹ Department of Oncology, Royal Free and University College Medical School, University College London, London, United Kingdom; ² Cancer Research UK Drug-DNA Interactions Research Group, ³ Department of Chemistry, Furman University, Greenville, South Carolina; ⁴ Dipartimento di Scienze Biomolecolari e Biotecnologie, Universita degli Studi di Milano, Milan, Italy; and ⁵ Department of Chemistry, Division of Natural Sciences, Hope College, Holland, Michigan

Requests for reprints: Daniel Hochhauser, Department of Oncology, Royal Free and University College Medical School, University College London, 91 Riding House Street, London W1W 7BS, United Kingdom. Phone: 44-20-7679-9326; Fax: 44-20-7436-2956. E-mail: d.hochhauser{at}ucl.ac.uk

Abstract

Topoisomerase II (topo II) is an important target for several chemotherapeutic agents, including etoposide and doxorubicin. Confluent cells express low levels of topo II and are resistant to etoposide treatment. Repression of transcription in confluent cells is mediated by binding of the transcription factor NF-Y to inverted CCAAT motifs within the topo II promoter. To block the repressive binding of NF-Y, a polyamide (JH-37) was designed to bind to the flanking regions of selected CCAAT sites within the topo II promoter. Electrophoretic mobility shift assays and DNase I footprinting assays showed occupancy of the inverted CCAAT sites by JH-37. Chromatin immunoprecipitation assays confirmed in vivo inhibition of NF-Y binding to the topo II promoter. Following incubation of confluent NIH3T3 cells with JH-37, increased expression of topo II mRNA and protein was detectable. This correlated both with increased DNA double-strand breaks as shown by comet assay and decreased cell viability following exposure to etoposide. Polyamides can modulate gene expression and chemosensitivity of cancer cells. [Mol Cancer Ther 2007;6(1):346–54]

Grant support: Medical Research Council Career Establishment grant G0000168 (D. Hochhauser), Arnold and Mabel Beckman Foundation (Beckman Scholar Program for D. Harris), GlaxoSmithKline Summer Research Fellowship (Z. Taherbhai), and National Science Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/16/06; revised 10/ 4/06; accepted 11/10/06.

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