Mutant p53 and aberrant cytosine methylation cooperate to silence gene expression.
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.
Oshiro
Marc M
MM
Bone Marrow Transplant Program, Arizona Cancer Center and Department of Pharmacology & Toxicology, The University of Arizona, Tucson, AZ 85724, USA.
Watts
George S
GS
Wozniak
Ryan J
RJ
Junk
Damian J
DJ
Munoz-Rodriguez
Jose L
JL
Domann
Frederick E
FE
Futscher
Bernard W
BW
D001374:Azacitidine / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D002843:Chromatin / Q000378:metabolism / Q000648:ultrastructure; D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects; D015257:DNA-Cytosine Methylases / Q000378:metabolism; D051187:Desmocollins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics; D015843:Serpins / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D002843:Chromatin; C490356:DSC3 protein, human; D051187:Desmocollins; D006657:Histones; D008562:Membrane Glycoproteins; D011506:Proteins; C085344:SERPIN-B5; D015843:Serpins; D016159:Tumor Suppressor Protein p53; D003596:Cytosine; C029641:DNA modification methylase HpaII; D015257:DNA-Cytosine Methylases; D001374:Azacitidine