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Evidence for a cancer-specific switch at the CDK4 promoter with loss of control by both USF and c-Myc

Oncogene volume 23, pages 6125–6135 (2004)Cite this article

Abstract

USF and c-Myc are basic helix–loop–helix transcription factors with similar DNA-binding specificities, but antagonistic effects on cellular transformation. In order to determine how these opposite functions correlate with the transcriptional activities of the two factors on particular downstream targets, we investigated the roles of USF and c-Myc in expression of CDK4, a known direct target of c-Myc. Overexpression of either c-Myc or USF2, but not USF1, stimulated the expression of CDK4 promoter-driven reporter genes in the non-tumorigenic mammary epithelial MCF-10A cells. Dominant-negative mutants specific to either Myc or USF family proteins inhibited reporter gene activity as well as endogenous CDK4 expression, demonstrating involvement of both USF and Myc in CDK4 transcriptional control. In contrast, in two different breast cancer cell lines where USF is transcriptionally inactive and c-Myc is overexpressed, CDK4 promoter activity was no longer responsive to either transcription factor. Accordingly, chromatin immunoprecipitation revealed significantly lower levels of both USF and c-Myc bound to the endogenous CDK4 promoter in breast cancer cells than in MCF-10A cells, with a concomitant decrease in associated histone H3 acetylation. These results suggest that a major switch in the transcriptional control of CDK4 occurs during breast carcinogenesis, with likely alteration of cell cycle regulation.

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Acknowledgements

The technical help by Hui-Xin Yang for FACS analysis and immunoblotting is gratefully acknowledged. Grants 9866 from the Susan G Komen Breast Cancer Foundation, CA79578 from the National Institutes of Health, and G-1195 from the Robert A Welch Foundation supported this work. The MD Anderson Cancer Center DNA-sequencing and FACS facilities are supported by Grant CA16672.

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Authors and Affiliations

  1. Department of Molecular Genetics, The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, 77030, TX, USA

    Snehalata A Pawar, Marilyn N Szentirmay & Michèle Sawadogo

  2. Molecular Oncology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18A, Martinsried/Munich, D-82152, Germany

    Heiko Hermeking

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  1. Snehalata A Pawar
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Correspondence to Michèle Sawadogo.

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Pawar, S., Szentirmay, M., Hermeking, H. et al. Evidence for a cancer-specific switch at the CDK4 promoter with loss of control by both USF and c-Myc. Oncogene 23, 6125–6135 (2004). https://doi.org/10.1038/sj.onc.1207806

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