Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

• Published in: Cell death and differentiation Vol. 18; no. 7; pp. 1220 - 1230
• Main Authors: Huang, Y, Chuang, A, Hao, H, Talbot, C, Sen, T, Trink, B, Sidransky, D, Ratovitski, E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2011; Nature Publishing Group
• Subjects: 631/208/200; 631/337/384/331; 692/699/67/1059/99; 692/699/67/1536; Antineoplastic Agents - pharmacology; Apoptosis; Biochemistry; Biomedical and Life Sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Cell Biology; Cell Cycle Analysis; Cell Line, Tumor; Cisplatin - pharmacology; DEAD-box RNA Helicases - antagonists & inhibitors; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - metabolism; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - metabolism; Humans; Life Sciences; MicroRNAs - metabolism; Original Paper; Phosphorylation; Promoter Regions, Genetic; Protein Binding; Ribonuclease III - antagonists & inhibitors; Ribonuclease III - genetics; Ribonuclease III - metabolism; RNA Interference; RNA, Small Interfering - metabolism; Stem Cells; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; microRNA; squamous cell carcinomas; DICER1; p63; cisplatin
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2010.188

Head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin (CIS) displayed a dramatic ATM-dependent phosphorylation of ΔNp63 α that leads to the transcriptional regulation of downstream mRNAs. Here, we report that phospho (p)-ΔNp63 α transcriptionally deregulates miRNA expression after CIS treatment. Several p-ΔNp63 α -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-ΔNp63 α and mediate key pathways implicated in the response of cancer cells to chemotherapeutic drugs.