Phospho-ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation.
Cisplatin-induced and ATM-phosphorylated (p)-ΔNp63α 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-ΔNp63α bound to target gene promoters, and regulated the activity of the tested promoters in vitro. P-ΔNp63α 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 ΔNp63α, 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.
Head and Neck Cancer Research Division, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: eratovi1@jhmi.edu.
Edward A
EA
Ratovitski
D000970:Antineoplastic Agents / Q000494:pharmacology; D051400:Aquaporin 3 / Q000235:genetics* / Q000378:metabolism; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D020169:Caspases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D057167:Claudins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000970:Antineoplastic Agents; C508912:CLDN19 protein, human; D057167:Claudins; C552431:MIRN185 microRNA, human; D035683:MicroRNAs; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C487931:mirnlet7 microRNA, human; D051400:Aquaporin 3; C514086:ALOX12B protein, human; D001092:Arachidonate 12-Lipoxygenase; C506446:CASP14 protein, human; D020169:Caspases; D002945:Cisplatin
Apoptosis; Chemoresistance; Squamous cell carcinoma; microRNA; p63