Regulation of VDR by ΔNp63α is associated with inhibition of cell invasion

Abstract

The p63 transcription factor has a pivotal role in epithelial morphogenesis. Multiple transcripts of the TP63 gene are generated because of alternative promoter usage and splicing. DeltaNp63alpha is the predominant isoform of p63 observed during epithelial morphogenesis and in human cancers. Loss of DeltaNp63alpha expression has been shown to promote invasiveness in a subset of human cancer cell lines. Here, we studied whether the regulation of VDR by DeltaNp63alpha controls the invasiveness of an epidermoid cancer cell line. We demonstrate that VDR expression is induced by all p63 isoforms, including DeltaNp63alpha. Endogenous DeltaNp63alpha protein was observed to bind to the VDR promoter, and silencing of endogenous DeltaNp63alpha resulted in diminished VDR expression. Although silencing of p63 inhibits VDR expression leading to an increase in cell migration, overexpression of p63 or VDR results in reduced cell migration as a result of increased VDR expression. Therefore, it is conceivable that p63 inhibits cell invasion by regulating VDR expression. Finally, we observed that expression of p63 and VDR overlaps in the wild-type mouse skin, but a reduced or complete absence of VDR expression was observed in skin from p63-null mice and in p63-null mouse embryonic fibroblasts. In conclusion, we demonstrate a direct transcriptional regulation of VDR by DeltaNp63alpha. Our results highlight a crucial role for VDR in p63-mediated biological functions.