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Nucleic Acids Res. 2018 Oct 12;46(18):9578-9590. doi: 10.1093/nar/gky755.

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

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Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
Regenerative Medicine Center, University Medical Center Utrecht Uppsalalaan 6, Utrecht, The Netherlands.
Mechanisms of Transcription Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Cancer Research UK Cambridge Institute, and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, 3508 AB Utrecht, The Netherlands.
Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, 3484 EA Utrecht, The Netherlands.
Cancer Research UK Cancer Centre, Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK.


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.

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