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  • Original Paper
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Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression

Oncogene volume 22, pages 3624–3634 (2003)Cite this article

Abstract

p53 is an important transcriptional regulator that is frequently mutated in cancer. Gene-profiling experiments of breast cancer cells infected with wt p53 revealed both MASPIN and desmocollin 3 (DSC3) to be p53-target genes, even though both genes are silenced in association with aberrant cytosine methylation of their promoters. Despite the transcriptional repression of these genes by aberrant DNA methylation, restoration of p53 resulted in the partial reactivation of both genes. This reactivation is a result of wt p53 binding to its consensus DNA-binding sites within the MASPIN and DSC3 promoters, stimulating histone acetylation, and enhancing chromatin accessibility of their promoters. Interestingly, wt p53 alone did not affect the methylation status of either promoter, suggesting that p53 itself can partially overcome the repressive barrier of DNA methylation. Pharmacologic inhibition of DNA methylation with 5-aza-2′-deoxycytidine in combination with restoration of wt p53 status resulted in a synergistic reactivation of these genes to near-normal levels. These results suggest that cancer treatments that target both genetic and epigenetic facets of gene regulation may be a useful strategy towards the therapeutic transcriptional reprogramming of cancer cells.

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Acknowledgements

We thank Bert Vogelstein for the control and wt p53 adenoviruses. We thank S Vaught, A Palazzo, M Fitzgerald, and the Arizona Cancer Microarray Core for technical assistance. NIH grants to BWF and to FED, as well as to the Arizona Cancer Center and the Gene Therapy Center at the University of Iowa supported this work. MO was supported by a Cancer Biology Training grant from the NIH, and RW received support from a Toxicology Training grant from the NIEHS.

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Authors and Affiliations

  1. Arizona Cancer Center and Department of Pharmacology & Toxicology, Bone Marrow Transplant Program, The University of Arizona, Tucson, 85724, AZ, USA

    Marc M Oshiro, George S Watts, Ryan J Wozniak, Damian J Junk, Jose L Munoz-Rodriguez & Bernard W Futscher

  2. Department of Radiation Oncology, Free Radical & Radiation Biology Program and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, 52242, IA, USA

    Frederick E Domann

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  1. Marc M Oshiro
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Correspondence to Bernard W Futscher.

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Oshiro, M., Watts, G., Wozniak, R. et al. Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression. Oncogene 22, 3624–3634 (2003). https://doi.org/10.1038/sj.onc.1206545

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