Journal Article

Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β–SMAD3 pathway in non-small cell lung adenocarcinoma

Lorenzo Spaggiari, Michel Mittelbronn, Pier Paolo Di Fiore, Francescopaolo Iavarone, Serena Fernandez, Leila Dardaei, Patrick N. Harter, Nadia Mandia, Federica Pisati, Francesco Blasi, Francesco Talotta, Fabrizio Bianchi, Maurizio Risolino, Pasquale Verde, Dorothea Schulte, Elena Longobardi, Mariarosaria Incoronato

2014

Overview

Significance Epithelial–mesenchymal transition (EMT) is a transdifferentiation program implicated in tumor cell dissemination, controlled by networks of transcription complexes responsive to paracrine factors, such as TGF-β. Pre–B-cell leukemia homeobox (Pbx)-regulating protein-1 (PREP1) is a ubiquitous homeodomain transcription factor involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. PREP1 is a haploinsufficient oncosuppressor in mouse tumorigenesis. By characterizing PREP1 as a novel regulator of EMT in human lung adenocarcinoma, we show that PREP1 also harbors prometastatic properties. While autosustaining its activity by stabilizing its transcriptional partner PBX1, PREP1 modulates the responsiveness of lung cancer cells to TGF-β by controlling the expression of two proinvasive transcription factors (SMAD3 and Fos-related antigen 1) implicated in metastasis mechanisms. Thus, PREP1 represents a novel, promising therapeutic target in non-small cell lung cancer.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - pathology / Adenocarcinoma of Lung / Animals / antigens / Biological Sciences / Brain Neoplasms - pathology / Brain Neoplasms - secondary / carcinogenesis / Carcinoma, Non-Small-Cell Lung - genetics / Carcinoma, Non-Small-Cell Lung - pathology / Cell Line, Tumor / Cell Movement - drug effects / Cell Nucleus - drug effects / Cell Nucleus - metabolism / Cell Proliferation - drug effects / DNA-Binding Proteins - metabolism / early development / Enhancer Elements, Genetic - genetics / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Gene Expression Regulation, Neoplastic - drug effects / hematopoiesis / Homeodomain Proteins - metabolism / Humans / insulin resistance / Introns - genetics / leukemia / lung neoplasms / Lung Neoplasms - genetics / Lung Neoplasms - pathology / metastasis / Mice / Models, Biological / neoplasm cells / Neoplasm Metastasis / Peptide Hydrolases - metabolism / PNAS Plus / Pre-B-Cell Leukemia Transcription Factor 1 / Protein Binding - drug effects / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-fos - metabolism / Signal Transduction - drug effects / Signal Transduction - genetics / Smad3 Protein - genetics / Smad3 Protein - metabolism / Survival Analysis / transcription (genetics) / Transcription Factor AP-1 - metabolism / transcription factors / Transcription, Genetic - drug effects / transforming growth factor beta / Transforming Growth Factor beta - metabolism / Transforming Growth Factor beta - pharmacology