SOX4 can redirect TGF-β-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis

• Published in: Nucleic acids research Vol. 46; no. 18; pp. 9578 - 9590
• Main Authors: Vervoort, Stephin J, Lourenço, Ana Rita, Tufegdzic Vidakovic, Ana, Mocholi, Enric, Sandoval, José L, Rueda, Oscar M, Frederiks, Cynthia, Pals, Cornelieke, Peeters, Janneke G C, Caldas, Carlos, Bruna, Alejandra, Coffer, Paul J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 12.10.2018
• Subjects: Breast Neoplasms - genetics; Breast Neoplasms - pathology; Carcinogenesis - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Molecular Biology; Prognosis; Signal Transduction; Smad3 Protein - genetics; SOXC Transcription Factors - genetics; Transcription, Genetic; Transforming Growth Factor beta - genetics
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gky755

Abstract Expression of the transcription factor SOX4 is often elevated in human cancers, where it generally correlates with tumor-progression and poor-disease outcome. Reduction of SOX4 expression results in both diminished tumor-incidence and metastasis. In breast cancer, TGF-β-mediated induction of SOX4 has been shown to contribute to epithelial-to-mesenchymal transition (EMT), which controls pro-metastatic events. Here, we identify SMAD3 as a novel, functionally relevant SOX4 interaction partner. Genome-wide analysis showed that SOX4 and SMAD3 co-occupy a large number of genomic loci in a cell-type specific manner. Moreover, SOX4 expression was required for TGF-β-mediated induction of a subset of SMAD3/SOX4-co-bound genes regulating migration and extracellular matrix-associated processes, and correlating with poor-prognosis. These findings identify SOX4 as an important SMAD3 co-factor controlling transcription of pro-metastatic genes and context-dependent shaping of the cellular response to TGF-β. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-β signaling, thereby impairing tumorigenesis.