Abstract
In addition to its classical roles as a tumor suppressor, p53 has also been shown to act as a guardian of epithelial integrity by inducing the microRNAs that target transcriptional factors driving epithelial–mesenchymal transition. On the other hand, the ENCODE project demonstrated an enrichment of putative motifs for the binding of p53 in epithelial-specific enhancers, such as CDH1 (encoding E-cadherin) enhancers although its biological significance remained unknown. Recently, we identified two novel modes of epithelial integrity (i.e., maintenance of CDH1 expression): one involves the binding of p53 to a CDH1 enhancer region and the other does not. In the former, the binding of p53 is necessary to maintain permissive histone modifications around the CDH1 transcription start site, whereas in the latter, p53 does not bind to this region nor affect histone modifications. Furthermore, these mechanisms likely coexisted within the same tissue. Thus, the mechanisms involved in epithelial integrity appear to be much more complex than previously thought. In this review, we describe our findings, which may instigate further experimental scrutiny towards understanding the whole picture of epithelial integrity as well as the related complex asymmetrical functions of p53. Such understanding will be important not only for cancer biology but also for the safety of regenerative medicine.
Highlights
Epithelial cells may undergo epithelial–mesenchymal transition (EMT) in order to change into highly motile and invasive phenotypes as well as to move out from the original tissue, such as during development, in a manner that is dependent on environmental signals [1,2]
We recently found that p53 binds to the nucleotides of the CDH1 enhancer of some epithelial cells, with this binding being necessary to maintain CDH1 expression [30]
We showed that the binding of p53 is necessary to maintain high levels of histone H3K27 acetylation (H3K27ac) of the CDH1 locus, in which p53 appears to antagonize Enhancer of Zeste Homolog 2 (EZH2) activity, a catalytic subunit of PRC2, which otherwise catalyzes the trimethylation of H3K27 (H3K27me3)
Summary
Epithelial cells may undergo epithelial–mesenchymal transition (EMT) in order to change into highly motile and invasive phenotypes as well as to move out from the original tissue, such as during development, in a manner that is dependent on environmental signals [1,2]. Given the cell context-dependent functions of these EMT-TFs [19,20] and the significant enrichment of the motifs for the binding of p53 in the epithelial-specific enhancers [21,22,23], p53 might have additional mechanisms by which it maintains epithelial integrity. No of p53-Binding Motifs across the Gene Locus (No. Recent studies have clarified another potential p53 function, which involves the regulation of the epigenome by controlling DNA methylation, histone methylation/acetylation and non-coding RNAs. DNA methylation statuses in mouse embryonic stem cells (ESCs) were shown to be uncontrollable in the absence of p53, resulting in the generation of intraclonal heterogeneity [28]. Neat was recently identified as a p53-induced lincRNA and its deficiency was shown to cause malignancy of pancreatic ductal adenocarcinoma (PDAC) through the global changes in gene expression [47]
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