Transcription Factors OVOL1 and OVOL2 Induce the Mesenchymal to Epithelial Transition in Human Cancer

• Published in: PloS one Vol. 8; no. 10; p. e76773
• Main Authors: Roca, Hernan, Hernandez, James, Weidner, Savannah, McEachin, Richard C., Fuller, David, Sud, Sudha, Schumann, Taibriana, Wilkinson, John E., Zaslavsky, Alexander, Li, Hangwen, Maher, Christopher A., Daignault-Newton, Stephanie, Healy, Patrick N., Pienta, Kenneth J.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04.10.2013; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Bioinformatics; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cancer metastasis; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cluster Analysis; Coculture Techniques; Control theory; Disease Models, Animal; DNA binding proteins; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition; Feedback loops; Female; Gene expression; Gene Expression Profiling; Genotype & phenotype; Heterografts; Humans; Internal medicine; Macrophages - metabolism; Male; Medicine; Mesenchyme; Metastases; Metastasis; Mice; MicroRNAs; Microscopy; Morphology; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Plastic properties; Plasticity; Prostate cancer; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteins; Regulators; RNA; RNA Splicing; Splicing; Stem cells; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Tumor cell lines; Urology; Ann Arbor Michigan; United States > US; Michigan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0076773

Cell plasticity regulated by the balance between the mesenchymal to epithelial transition (MET) and the opposite program, EMT, is critical in the metastatic cascade. Several transcription factors (TFs) are known to regulate EMT, though the mechanisms of MET remain unclear. We demonstrate a novel function of two TFs, OVOL1 and OVOL2, as critical inducers of MET in human cancers. Our findings indicate that the OVOL-TFs control MET through a regulatory feedback loop with EMT-inducing TF ZEB1, and the regulation of mRNA splicing by inducing Epithelial Splicing Regulatory Protein 1 (ESRP1). Using mouse prostate tumor models we show that expression of OVOL-TFs in mesenchymal prostate cancer cells attenuates their metastatic potential. The role of OVOL-TFs as inducers of MET is further supported by expression analyses in 917 cancer cell lines, suggesting their role as crucial regulators of epithelial-mesenchymal cell plasticity in cancer.