Phospho-ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation

Cisplatin-induced and ATM-phosphorylated (p)-Delta Np63 alpha regulates the expression of epidermal differentiation and skin barrier regulators (AQP3, CASP14, ALOX12B, and CLDN1) in squamous cell carcinoma (SCC) cells by dual transcriptional and post-transcriptional mechanisms. We found that p-Delta Np63 alpha bound to target gene promoters, and regulated the activity of the tested promoters in vitro. P-Delta Np63 alpha was shown to upregulate miR-185-5p and downregulate let7-5p, which subsequently modulated AQP3, CASP14, ALOX12B and CLDN1 through their respective 3'-untranslated regions. The introduction of miR-185-5p into resistant SCC-11M cells, which are unable to phosphorylate Delta Np63 alpha, render these cells more sensitive to cisplatin treatment. Further studies of the AQP3, CASP14, ALOX12B, and CLDN1 contributions to chemoresistance may assist in developing novel microRNA-based therapies for human SCC. (C) 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.