Abstract
Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ΔNp63α and β isoforms, leaving only ΔNp63γ, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ΔNp63α isoform. We also show that ΔNp63γ expressed in a background where all the other ΔNp63 are knocked down causes EMT with an increase in TGFβ-1, -2, and -3 and downstream effectors Smads2/3/4. In addition, a p63 binding site in intron 1 of TGFβ was identified. Inhibition of the TGFβ response with a specific inhibitor results in reversion of EMT in ΔNp63α- and β-depleted cells. In summary, we show that p63 is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.
Highlights
The transcription factor p63 is a member of the p53 gene family
Knockdown of p63␣ and  Isoforms Results in an epithelial to mesenchymal transition (EMT) Phenotype—The p63 isoforms expressed in MCF10A cells were determined by real time PCR and the estimated copy number of each of p63␣,  and ␥ isoforms was 846, 23 and 3 per 10 g of RNA compared with linearized plasmid standards
The p63 gene has been shown to have a central role in the development of stratified epithelium, and p63 plays a role in cancer
Summary
The transcription factor p63 is a member of the p53 gene family. At least six isoforms are expressed as a result of two alternative promoters giving rise to transactivating (TA)2 isoforms, containing a transactivation domain at the amino terminus and ⌬N isoforms that lack this domain [1, 2]. We show that depletion of the ⌬Np63␣ and  isoforms, leaving only ⌬Np63␥, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. Depletion of the ⌬Np63␣ and  isoforms resulted in a change in morphology of MCF10A cells reminiscent of EMT (Fig. 1A, UTR).
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