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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Vervoort, Stephin J 
Lourenço, Ana Rita 
Tufegdzic Vidakovic, Ana 
Mocholi, Enric 
Sandoval, José L 

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.

Description

Keywords

Breast Neoplasms, Carcinogenesis, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, MCF-7 Cells, Prognosis, SOXC Transcription Factors, Signal Transduction, Smad3 Protein, Transcription, Genetic, Transforming Growth Factor beta

Journal Title

Nucleic Acids Res

Conference Name

Journal ISSN

0305-1048
1362-4962

Volume Title

46

Publisher

Oxford University Press (OUP)
Sponsorship
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research UK (unknown)
Cancer Research Uk (None)
Cancer Research UK (unknown)
Cancer Research UK (60098573)
Cancer Research UK (unknown)
Cancer Research UK (CB4140)
Cancer Research UK (C14303/A17197)