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Transcription factor PREP1 induces EMT and metastasis by controlling the TGF-β-SMAD3 pathway in non-small cell lung adenocarcinoma.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Sep 09; Vol. 111 (36), pp. E3775-84. Date of Electronic Publication: 2014 Aug 25. - Publication Year :
- 2014
-
Abstract
- Pre-B-cell leukemia homeobox (Pbx)-regulating protein-1 (Prep1) is a ubiquitous homeoprotein involved in early development, genomic stability, insulin sensitivity, and hematopoiesis. Previously we have shown that Prep1 is a haploinsufficient tumor suppressor that inhibits neoplastic transformation by competing with myeloid ecotropic integration site 1 for binding to the common heterodimeric partner Pbx1. Epithelial-mesenchymal transition (EMT) is controlled by complex networks of proinvasive transcription factors responsive to paracrine factors such as TGF-β. Here we show that, in addition to inhibiting primary tumor growth, PREP1 is a novel EMT inducer and prometastatic transcription factor. In human non-small cell lung cancer (NSCLC) cells, PREP1 overexpression is sufficient to trigger EMT, whereas PREP1 down-regulation inhibits the induction of EMT in response to TGF-β. PREP1 modulates the cellular sensitivity to TGF-β by inducing the small mothers against decapentaplegic homolog 3 (SMAD3) nuclear translocation through mechanisms dependent, at least in part, on PREP1-mediated transactivation of a regulatory element in the SMAD3 first intron. Along with the stabilization and accumulation of PBX1, PREP1 induces the expression of multiple activator protein 1 components including the proinvasive Fos-related antigen 1 (FRA-1) oncoprotein. Both FRA-1 and PBX1 are required for the mesenchymal changes triggered by PREP1 in lung tumor cells. Finally, we show that the PREP1-induced mesenchymal transformation correlates with significantly increased lung colonization by cells overexpressing PREP1. Accordingly, we have detected PREP1 accumulation in a large number of human brain metastases of various solid tumors, including NSCLC. These findings point to a novel role of the PREP1 homeoprotein in the control of the TGF-β pathway, EMT, and metastasis in NSCLC.
- Subjects :
- Adenocarcinoma genetics
Adenocarcinoma of Lung
Animals
Brain Neoplasms pathology
Brain Neoplasms secondary
Carcinoma, Non-Small-Cell Lung genetics
Cell Line, Tumor
Cell Movement drug effects
Cell Nucleus drug effects
Cell Nucleus metabolism
Cell Proliferation drug effects
DNA-Binding Proteins metabolism
Enhancer Elements, Genetic genetics
Gene Expression Regulation, Neoplastic drug effects
Humans
Introns genetics
Lung Neoplasms genetics
Mice
Models, Biological
Neoplasm Metastasis
Peptide Hydrolases metabolism
Pre-B-Cell Leukemia Transcription Factor 1
Protein Binding drug effects
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-fos metabolism
Smad3 Protein genetics
Survival Analysis
Transcription Factor AP-1 metabolism
Transcription, Genetic drug effects
Transforming Growth Factor beta pharmacology
Adenocarcinoma pathology
Carcinoma, Non-Small-Cell Lung pathology
Epithelial-Mesenchymal Transition drug effects
Epithelial-Mesenchymal Transition genetics
Homeodomain Proteins metabolism
Lung Neoplasms pathology
Signal Transduction drug effects
Signal Transduction genetics
Smad3 Protein metabolism
Transforming Growth Factor beta metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 25157139
- Full Text :
- https://doi.org/10.1073/pnas.1407074111