p63 Attenuates Epithelial to Mesenchymal Potential in an Experimental Prostate Cell Model

Abstract

The transcription factor p63 is central for epithelial homeostasis and development. In our model of epithelial to mesenchymal transition (EMT) in human prostate cells, p63 was one of the most down-regulated transcription factors during EMT. We therefore investigated the role of p63 in EMT. Over-expression of the predominant epithelial isoform ΔNp63α in mesenchymal type cells of the model led to gain of several epithelial characteristics without resulting in a complete mesenchymal to epithelial transition (MET). This was corroborated by a reciprocal effect when p63 was knocked down in epithelial EP156T cells. Global gene expression analyses showed that ΔNp63α induced gene modules involved in both cell-to-cell and cell-to-extracellular-matrix junctions in mesenchymal type cells. Genome-wide analysis of p63 binding sites using ChIP-seq analyses confirmed binding of p63 to regulatory areas of genes associated with cell adhesion in prostate epithelial cells. DH1 and ZEB1 are two elemental factors in the control of EMT. Over-expression and knock-down of these factors, respectively, were not sufficient alone or in combination with ΔNp63α to reverse completely the mesenchymal phenotype. The partial reversion of epithelial to mesenchymal transition might reflect the ability of ΔNp63α, as a key co-ordinator of several epithelial gene expression modules, to reduce epithelial to mesenchymal plasticity (EMP). The utility of ΔNp63α expression and the potential of reduced EMP in order to counteract metastasis warrant further investigation.

Low‐grade spindle cell proliferation in clear cell renal cell carcinoma is unlikely to be an initial step in sarcomatoid differentiation

“…Repression of p63, a transcription factor required for maintenance of epithelial cell differentiation, induces EMT. [18][19][20] Morphologically, LG-SCP areas in our ccRCC cases appeared to derive directly from 'conventional' clear cell elements. There was a continual spectrum of gradually elongated clear cells to fully developed slender spindle cells with low-grade nuclei.…”

“…Claudins are suggested to be integral membrane proteins, responsible for maintaining epithelial cell polarity. Repression of p63, a transcription factor required for maintenance of epithelial cell differentiation, induces EMT …”

Role of Epithelial Mesenchymal Transition in Prostate Tumorigenesis

“…It was found that the effects of p63 on EMT markers are mediated mainly through miR-205 and p53 mutations [118], because mutant p53 can suppress the actions of p63. It has been reported that p63 is highly down-regulated when epithelial EP156T cells underwent EMT to become EPT1 cells [119] and over-expression of ΔNp63 in mesenchymal type cells led to gain of several epithelial characteristics [120, 121]. …”

Systematic enrichment analysis of potentially functional regions for 103 prostate cancer risk-associated loci

“…Genomic regions with potential functional impact were obtained from two major sources: annotated databases from UCSC table browser and published ChIP-Seq data from any prostate-derived cell lines or prostate tissue samples before available May 2014 [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. These genomic regions were grouped into three categories: 1) coding regions defined by UCSC, including exons defined by the Consensus Coding Sequence (CCDS) project and coding regions for small nuclear RNA (snoRNA)/ micro RNA (miRNA) defined by miRBase and snoR-NABase, 2) regulatory elements defined by UCSC, including CpG island, ORegAnno, polyaDb, switchDbTss, targetscans and Vistaenhancers, and 3) binding regions defined by ChIP-Seq, including those for transcription factors (TFs), histone modifications (HMs), DNase I hypersensitivity (DHSs) and RNA Polymerase IIA (POLR2A).…”

“…Recently, 23 additional PCa risk-associated SNPs were discovered by evaluating more than 10 million SNPs across the genome among 43,303 PCa cases and 43,737 controls from the international PRACTICAL Consortium [20]. In the meantime, more functionally annotated genomic regions have been identified by various ChIP-Seq analyses in prostate cell lines and tissues such as LNCaP, VCaP, RWPE1, 22Rv1, and PC3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. These additional pieces of information improve our ability to understand the location of PCa risk SNPs in relationship with functionally annotated regions in the genome.…”