MicroRNA-128-2 targets the transcriptional repressor E2F5 enhancing mutant p53 gain of function

• Published in: Cell death and differentiation 2012-06, Vol.19 (6), p.1038-1048
• Main Authors: Donzelli, S, Fontemaggi, G, Fazi, F, Di Agostino, S, Padula, F, Biagioni, F, Muti, P, Strano, S, Blandino, G
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Biology; Cell Cycle Analysis; Cell death; Cell Line, Tumor; Chemoresistance; Cisplatin; Cisplatin - pharmacology; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; E2F5 Transcription Factor - metabolism; Fluorouracil - pharmacology; Gene expression; Humans; Life Sciences; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; MicroRNAs; MicroRNAs - metabolism; miRNA; Mutation; Original Paper; p53 protein; Phosphoproteins - genetics; Phosphoproteins - metabolism; Post-transcription; Promoter Regions, Genetic; Promoters; Proteins; Repressors; RNA, Messenger - metabolism; Stem Cells; Transcription; Transcription factors; Transcription, Genetic; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.190

p53 mutations have profound effects on non-small-cell lung cancer (NSCLC) resistance to chemotherapeutic treatments. Mutant p53 proteins are usually expressed at high levels in tumors, where they exert oncogenic functions. Here we show that p53R175H, a hotspot p53 mutant, induces microRNA (miRNA)-128-2 expression. Mutant p53 binds to the putative promoter of miR128-2 host gene, ARPP21 , determining a concomitant induction of ARPP21 mRNA and miR-128-2. miR-128-2 expression in lung cancer cells inhibits apoptosis and confers increased resistance to cisplatin, doxorubicin and 5-fluorouracyl treatments. At the molecular level, miR-128-2 post-transcriptionally targets E2F5 and leads to the abrogation of its repressive activity on p21 waf1 transcription. p21 waf1 protein localizes to the cytoplasmic compartment, where it exerts an anti-apoptotic effect by preventing pro-caspase-3 cleavage. This study emphasizes miRNA-128-2 role as a master regulator in NSCLC chemoresistance.