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


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-?-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-?-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-?. Targeted disruption of the interaction between these factors may have the potential to disrupt pro-oncogenic TGF-? signaling, thereby impairing tumorigenesis.

SUBMITTER: Vervoort SJ 

PROVIDER: S-EPMC6182182 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Vervoort Stephin J SJ   Lourenço Ana Rita AR   Tufegdzic Vidakovic Ana A   Mocholi Enric E   Sandoval José L JL   Rueda Oscar M OM   Frederiks Cynthia C   Pals Cornelieke C   Peeters Janneke G C JGC   Caldas Carlos C   Bruna Alejandra A   Coffer Paul J PJ  

Nucleic acids research 20181001 18


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. Geno  ...[more]

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