title: ZEB1 and TCF4 reciprocally modulate their transcriptional activities to regulate Wnt target gene expression.
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.
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Sánchez-Tilló
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: O
authors.initials: O
authors.lastname: de Barrios
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Valls
authors.affiliation: Department of Oral Immunology and Infectious Diseases and Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Darling
authors.affiliation: Institute of Metabolic and Digestive Diseases, Hospital Clinic, Barcelona, Spain.|Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Castells
authors.affiliation: Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, Barcelona, Spain.|Gastrointestinal and Pancreatic Oncology Team, Biomedical Research Networking Centers in Hepatic and Digestive Diseases (CIBERehd), Carlos III Health Institute (ISCIII), Barcelona, Spain.|James Graham Brown Cancer Center, Louisville, KY, USA.|ICREA, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Postigo
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018398:Homeodomain Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D051176:beta Catenin