Abstract
TP53 mutation (i.e., loss of normal-p53) may evoke epithelial-mesenchymal transition (EMT), which was previously attributed to loss of certain miRNAs. However, not all epithelial cells undergo EMT upon TP53 mutation, and the p53-miRNA axis may not fully explain p53 function in epithelial integrity. We here show two modes of epithelial integrity: one involves p53-binding to a nucleotide region and the other does not. In the former, p53 binds to the CDH1 (encoding E-cadherin) locus to antagonize EZH2-mediated H3K27 trimethylation (H3K27me3) to maintain high levels of acetylation of H3K27 (H3K27ac). In the latter, the same locus is not highly acetylated at H3K27, and does not allow p53-binding, nor needs to antagonize EZH2. We moreover demonstrated that although the CDH1 locus in the p53-independent cells, but not in fibroblasts, becomes high-H3K27ac by butyrate and allows p53-biniding, their CDH1 expression does not become dependent on p53. Our results identified novel modes of the epithelial integrity, in which the same epithelial-specific gene locus exhibits different requirement for p53 with different histone modifications among different epithelial cells to warrant its expression.
Highlights
P53, the TP53 gene product, is a pleiotropic protein with functions that appear to culminate in maintaining genome integrity, such as by acting as a transcriptional cofactor[1], regulating cellular metabolic reprograming to maintain antioxidative statuses[2,3,4,5,6], and sometimes by eliminating severely damaged cells[7]
Western blots were cropped for clarity; uncropped images are shown in Supplementary Figure S5
We found that p53 appears to be essential for E-cadherin expression in A549 lung cancer cells, in which siRNA-mediated silencing of TP53 abolished the E-cadherin expression (Fig. 1A)
Summary
P53, the TP53 gene product, is a pleiotropic protein with functions that appear to culminate in maintaining genome integrity, such as by acting as a transcriptional cofactor[1], regulating cellular metabolic reprograming to maintain antioxidative statuses[2,3,4,5,6], and sometimes by eliminating severely damaged cells[7]. As for a molecular mechanism therein involved, it was shown previously that normal-p53 has a potential to induce certain microRNAs (miRNAs) that target mRNAs encoding transcription factors (TFs) driving epithelial-mesenchymal transition (EMT), such as ZEB1, SNAI1, and BMI110,11. It is well documented that not all epithelial cells undergo EMT upon loss of normal-p5312,13. We identified a novel mechanism by which p53 acts to maintain CDH1 expression and the epithelial integrity. Our results suggested that in addition to the p53-miRNA axis, at least two other mechanisms exist with regard to maintaining CDH1 expression in epithelial cells, which may be important to block unnecessary onset of EMT. Western blots were cropped for clarity; uncropped images are shown in Supplementary Figure S5
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