TY - JOUR
T1 - SOX4 can redirect TGF-β-mediated SMAD3-transcriptional output in a context-dependent manner to promote tumorigenesis
AU - Vervoort, Stephin J.
AU - Lourenço, Ana Rita
AU - Tufegdzic Vidakovic, Ana
AU - Mocholi, Enric
AU - Sandoval, José L.
AU - Rueda, Oscar M.
AU - Frederiks, Cynthia
AU - Pals, Cornelieke
AU - Peeters, Janneke G.C.
AU - Caldas, Carlos
AU - Bruna, Alejandra
AU - Coffer, Paul J.
N1 - Funding Information:
The authors thank Peter ten Dijke for providing the SMAD-constructs, Bernard Perreira, Jason Carroll, Michal Mokry, Ruben van Boxtel, Jorg van Loosdregt and Coffer Lab members for helpful discussions. Dutch Cancer Foundation Grants [KWF UU 2013-5801, KWF UU 2015-7838]; Cancer Research UK and Fundação para a Ciência e a Tecnologia (FCT) fellowships (to J.L.S., A.R.L.). Funding for open access charge: KWF.
Publisher Copyright:
© The Author(s) 2018.
PY - 2018/10/12
Y1 - 2018/10/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85054897588
U2 - 10.1093/nar/gky755
DO - 10.1093/nar/gky755
M3 - Article
C2 - 30137431
SN - 0305-1048
VL - 46
SP - 9578
EP - 9590
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 18
ER -