DNA methylation inhibits p53-mediated survivin repression

Abstract

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 reexpression of tumor suppressor genes. However, our results indicate that an additional important mechanism is to decrease the expression of oncogenes.

Local Depletion of DNA Methylation Identifies a Repressive p53 Regulatory Region in the NEK2 Promoter

“…In a previous study, we observed p53-dependent repression of NEK2 following treatment with 5aza-dC (8). Here, we report that NEK2 is repressed by wild-type p53 and that loss of p53 results in local accumulation of DNA methylation.…”

“…Additional RT-qPCR primer sequences are listed in supplemental Table 1. The assays were performed at the Quantitative Genomics Core Laboratory (University of TexasHouston Medical School) using a 7700 Sequence Detector (Applied Biosystems) as described previously (8). Transcripts were quantified using the ⌬⌬Ct method, normalizing to 18 S rRNA or ␤-actin mRNA.…”

Epigenetic plasticity of hTERT gene promoter determines retinoid capacity to repress telomerase in maturation-resistant acute promyelocytic leukemia cells

“…[22][23][24] Such a mechanism of de-repression as a result of epigenetic regulation by DNA methylation has recently been shown for survivin. 51 In this study, methylation of survivin promoter inhibits the binding of p53, a repressor of its expression. In keeping, earlier studies showed that methylation of the hTERT promoter at the CTCF-binding site inhibited the binding of CTCF, thus derepressing hTERT in some human tumors.…”

Distinct p53 genomic binding patterns in normal and cancer-derived human cells

“…This in vivo binding preference is supported by a recent study which showed that in endometrial tumor samples, CGI promoter methylation at survivin/BIRC5 prevented p53 from binding. 66 Cancer development is known to be associated with substantial epigenetic changes, DNA hypomethylation on in IMR90, their distributions remain clearly different from the cancer data sets (Fig. S8).…”