title: Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells.
abstract: Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of ΔNp63α that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-ΔNp63α transcriptionally deregulates miRNA expression after CIS treatment. Several p-ΔNp63α-dependent microRNA species (miRNAs) were deregulated in HNSCC cells upon CIS exposure, including miR-181a, miR-519a, and miR-374a (downregulated) and miR-630 (upregulated). Deregulation of miRNA expression led to subsequent modulation of mRNA expression of several targets (TP53-S46, HIPK2, ATM, CDKN1A and 1B, CASP3, PARP1 and 2, DDIT1 and 4, BCL2 and BCL2L2, TP73, YES1, and YAP1) that are involved in the apoptotic process. Our data support the notion that miRNAs are critical downstream targets of p-ΔNp63α and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.
authors.affiliation: Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: Chuang
authors.forename: H
authors.initials: H
authors.lastname: Hao
authors.forename: C
authors.initials: C
authors.lastname: Talbot
authors.forename: T
authors.initials: T
authors.lastname: Sen
authors.forename: B
authors.initials: B
authors.lastname: Trink
authors.forename: D
authors.initials: D
authors.lastname: Sidransky
authors.forename: E
authors.initials: E
authors.lastname: Ratovitski
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D043244:Ribonuclease III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C546194:MIRN519 microRNA, human; C548399:MIRN630 microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; D002945:Cisplatin