title: Phospho-ΔNp63α/microRNA network modulates epigenetic regulatory enzymes in squamous cell carcinomas.
abstract: The tumor protein (TP) p63/microRNAs functional network may play a key role in supporting the response of squamous cell carcinomas (SCC) to chemotherapy. We show that the cisplatin exposure of SCC-11 cells led to upregulation of miR-297, miR-92b-3p, and miR-485-5p through a phosphorylated ΔNp63α-dependent mechanism that subsequently modulated the expression of the protein targets implicated in DNA methylation (DNMT3A), histone deacetylation (HDAC9), and demethylation (KDM4C). Further studies showed that mimics for miR-297, miR-92b-3p, or miR-485-5p, along with siRNA against and inhibitors of DNMT3A, HDAC9, and KDM4C modulated the expression of DAPK1, SMARCA2, and MDM2 genes assessed by the quantitative PCR, promoter luciferase reporter, and chromatin immunoprecipitation assays. Finally, the above-mentioned treatments affecting epigenetic enzymes also modulated the response of SCC cells to chemotherapeutic drugs, rendering the resistant SCC cells more sensitive to cisplatin exposure, thereby providing the groundwork for novel chemotherapeutic venues in treating patients with SCC.
authors.affiliation: Head and Neck Cancer Research Division; Department of Otolaryngology/Head and Neck Surgery; The Johns Hopkins School of Medicine; Baltimore, MD USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Ratovitski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000378:metabolism; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D007822:Laryngeal Neoplasms / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D035683:MicroRNAs / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; C081876:CKAP4 protein, human; D008565:Membrane Proteins; D035683:MicroRNAs; D010750:Phosphoproteins; C084011:SMARCA2 protein, human; D014157:Transcription Factors; D056466:Histone Demethylases; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases; D006655:Histone Deacetylases; D002945:Cisplatin
keywords: DNA methylation; TP63; chemoresistance; epigenetic regulation; histone deacetylation; histone demethylation; microRNA; squamous cell carcinomas