DNA methylation inhibits p53-mediated survivin repression.
The molecular progression of endometrial cancer is poorly understood, and both genetic and epigenetic factors play a role. Survivin is a member of the inhibitor of apoptosis (IAP) gene family and contains a canonical CpG island that has been described as epigenetically regulated. As survivin is overexpressed in endometrial tumors, we hypothesized that hypomethylation could explain this expression pattern. Surprisingly, methylation-specific PCR and pyrosequencing showed that survivin was hypermethylated in endometrial tumors and correlated with increased survivin expression. We speculated that methylation could inhibit the binding of p53, a repressor of survivin expression. Our data indicates that demethylation of the survivin promoter by decitabine results in p53-dependent survivin repression and that p53 binding can be inhibited by DNA methylation. We are the first to report survivin de-repression by DNA methylation. We also present microarray data, which suggest that de-repression by methylation is a general mechanism of p53 regulation. Demethylation induced by decitabine is traditionally thought to be active in tumors by allowing the re-expression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.
Nabilsi
N H
NH
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center Houston, Houston, 77030, USA.
Broaddus
R R
RR
Loose
D S
DS
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D016889:Endometrial Neoplasms / Q000378:metabolism*; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D001374:Azacitidine