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ZEB1 and TCF4 reciprocally modulate their transcriptional activities to regulate Wnt target gene expression

Oncogene volume 34, pages 5760–5770 (2015)Cite this article

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Abstract

The canonical Wnt pathway (TCF4/β-catenin) has important roles during normal differentiation and in disease. Some Wnt functions depend on signaling gradients requiring the pathway to be tightly regulated. A key Wnt target is the transcription factor ZEB1 whose expression by cancer cells promotes tumor invasiveness by repressing the expression of epithelial specification markers and activating mesenchymal genes, including a number of Wnt targets such as LAMC2 and uPA. The ability of ZEB1 to activate/repress its target genes depends on its recruitment of corepressors (CtBP, BRG1) or coactivators (p300) although conditions under which ZEB1 binds these cofactors are not elucidated. Here, we show that TCF4 and ZEB1 reciprocally modulate each other’s transcriptional activity: ZEB1 enhances TCF4/β-catenin-mediated transcription and, in turn, Wnt signaling switches ZEB1 from a repressor into an activator. In colorectal cancer (CRC) cells with active Wnt signaling, ZEB1 enhances transcriptional activation of LAMC2 and uPA by TCF4/β-catenin. However, in CRC cells with inactive Wnt, ZEB1 represses both genes. Reciprocal modulation of ZEB1 and TCF4 activities involves their binding to DNA and mutual interaction. Wnt signaling turns ZEB1 into an activator by replacing binding of CtBP/BRG1 in favor of p300. Using a mouse model of Wnt-induced intestinal tumorigenesis, we found that downregulation of ZEB1 reduces the expression of LAMC2 in vivo. These results identify a mechanism through which Wnt and ZEB1 transcriptional activities are modulated, offering new approaches in cancer therapy.

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Acknowledgements

We are grateful to all researchers who provided us with reagents (see Materials and Methods and Supplementary Materials and Methods) and apologize to those whose work was cited indirectly through reviews owing to space limitations. This work was developed in the Centre de Recerca Biomèdica Cellex at IDIBAPS. The different parts of this study were independently funded by grants to AP from Fundació La Marató de TV3 (201330.10), Ministry of Economy and Competitiveness (BFU2010-15163 and SAF2014-52874- R), Leukemia Research Foundation, Academy of Medical and Health Sciences of Catalonia and the Balearic Islands, Avon Cosmetics S.A.U. (ACSAU), Catalan Agency for Management of University and Research Grants (AGAUR, 2014-SGR-475), European Commission of the European Union, Olga Torres Foundation, La Caixa Foundation (LCF), Spanish Association Against Cancer. EST’s salary was subsequently funded by grants from LCF, CIBERehd, ACSAU, and a Miguel Servet contract (MS13/00200) from Instituto de Salud Carlos III. OdB is recipient of a PhD scholarship from the Ministry of Education, Culture and Sports (FPU Program, AP2010-5489).

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Authors and Affiliations

  1. Department of Oncology and Hematology, Group of Transcriptional Regulation of Gene Expression, IDIBAPS, Barcelona, Spain

    E Sánchez-Tilló, O de Barrios, E Valls & A Postigo

  2. Department of Oral Immunology and Infectious Diseases and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA

    D S Darling

  3. Institute of Metabolic and Digestive Diseases, Hospital Clinic, Barcelona, Spain

    A Castells

  4. Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain

    A Castells & A Postigo

  5. James Graham Brown Cancer Center, Louisville, KY, USA

    A Postigo

  6. ICREA, Barcelona, Spain

    A Postigo

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  1. E Sánchez-Tilló
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Correspondence to A Postigo.

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Sánchez-Tilló, E., de Barrios, O., Valls, E. et al. ZEB1 and TCF4 reciprocally modulate their transcriptional activities to regulate Wnt target gene expression. Oncogene 34, 5760–5770 (2015). https://doi.org/10.1038/onc.2015.352

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