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

doi:10.1038/sj.onc.1206545

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Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression

Journal article

Peer reviewed

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 and Bernard W FUTSCHER

Oncogene, Vol.22(23), pp.3624-3634

2003

DOI: 10.1038/sj.onc.1206545

PMID: 12789271

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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.

Molecular Genetics

Fundamental and applied biological sciences. Psychology

Biological and medical sciences

Molecular and cellular biology

Genes. Genome

Details

Title: Subtitle: Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression
Creators: Marc M OSHIRO - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
George S WATTS - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
Ryan J WOZNIAK - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
Damian J JUNK - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
Jose L MUNOZ-RODRIGUEZ - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
Frederick E DOMANN - Department of Radiation Oncology, Free Radical & Radiation Biology Program and Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, United States
Bernard W FUTSCHER - Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, United States
Resource Type: Journal article
Publication Details: Oncogene, Vol.22(23), pp.3624-3634
DOI: 10.1038/sj.onc.1206545
PMID: 12789271
NLM abbreviation: Oncogene
ISSN: 0950-9232
eISSN: 1476-5594
Publisher: Nature Publishing; Basingstoke
Language: English
Date published: 2003
Academic Unit: Pathology; Surgery; Radiation Oncology
Record Identifier: 9984047602202771

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