Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression

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

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3624-3634
Number of pages11
JournalOncogene
Volume22
Issue number23
DOIs
StatePublished - Jun 5 2003

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Keywords

  • Azacytidine
  • Breast cancer
  • Maspin
  • Methylation
  • Tumor suppressor
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Oshiro, M. M., Watts, G. S., Wozniak, R. J., Junk, D. J., Munoz-Rodriguez, J. L., Domann, F. E., & Futscher, B. W. (2003). Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression. Oncogene, 22(23), 3624-3634. https://doi.org/10.1038/sj.onc.1206545