title: MCM7 and its hosted miR-25, 93 and 106b cluster elicit YAP/TAZ oncogenic activity in lung cancer.
abstract: Lung cancer is the first cause of cancer death worldwide and the Hippo pathway transcriptional coactivators YAP/TAZ have a pro-oncogenic role in this context. In order to understand the mechanisms through which YAP/TAZ elicit their oncogenic role in different systems, many studies are focused on YAP/TAZ target genes involved in the regulation of cell proliferation/survival and migration. However, there is scarce evidence on the role of YAP/TAZ in microRNA regulation while there is increasing evidence supporting the role of microRNAs in the main oncogenic processes. Here, we showed that YAP/TAZ were able to regulate several microRNAs in non-small cell lung cancer (NSCLC) cell lines. In detail, we focused on a cluster of three oncogenic microRNAs (miR-25, 93 and 106b) hosted in the MCM7 gene that were overexpressed in lung tumors compared to normal tissues. In addition, similar behavior was observed in breast cancer and head and neck tumor casuistries, where they showed a prognostic role. In NSCLC cells, YAP/TAZ induced the transcription of the MCM7 gene and its hosted miRs, thereby promoting cell proliferation through the post-transcriptional inhibition of the p21 cell cycle regulator. Accordingly, p21 was maintained at low levels in lung tumors compared to normal tissues. Conversely, its expression was restored in NSCLC cells upon YAP/TAZ interference or upon treatment with the statin cerivastatin. In summary, we provide evidence for a novel mechanism of modulation supporting the protumorigenic functions of the YAP/TAZ factors through the modulation of a bioncogenic locus consisting of one gene and three hosted microRNAs.
authors: Federica
authors: F
authors: Lo Sardo
authors: Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy.
authors: Mattia
authors: M
authors: Forcato
authors: Andrea
authors: A
authors: Sacconi
authors: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano 99, 34149, Trieste, Italy.
authors: Valeria
authors: V
authors: Capaci
authors: Department of Molecular Medicine, University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy.
authors: Francesca
authors: F
authors: Zanconato
authors: Silvia
authors: S
authors: Di Agostino
authors: Laboratorio Nazionale CIB (LNCIB), Area Science Park Padriciano 99, 34149, Trieste, Italy.|Dipartimento di Scienze della Vita-Università degli Studi di Trieste, 34127 Trieste, Italy.
authors: Giannino
authors: G
authors: Del Sal
authors: Division of Genetics Beth Israel Deaconess Medical Center, CLS Building, Room 401 330 Brookline Avenue Boston, MA 02215, USA and.
authors: Pier Paolo
authors: PP
authors: Pandolfi
authors: Molecular Chemoprevention Group, Molecular Medicine Area Regina Elena National Cancer Institute, via Elio Chianesi 53 00144, Rome, Italy.
authors: Sabrina
authors: S
authors: Strano
authors: Department of Life Sciences, Center for Genome Research, University of Modena and Reggio Emilia, via G. Campi 287, 41100 Modena, Italy.
authors: Silvio
authors: S
authors: Bicciato
authors: Giovanni
authors: G
authors: Blandino
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D064168:Minichromosome Maintenance Complex Component 7 / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C542541:MIRN106 microRNA, human; C543351:MIRN25 microRNA, human; C543350:MIRN93 microRNA, human; D035683:MicroRNAs; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C101624:MCM7 protein, human; D064168:Minichromosome Maintenance Complex Component 7