Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology; Faculty of Medicine and Health Sciences; Linköping University, Linköping, Sweden
Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology; Faculty of Medicine and Health Sciences; Linköping University, Linköping, Sweden
Salome Brütsch
Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland
Nikolaos Doumpas
Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland
Jan Reichmuth
Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland
Fabienne Murphy-Seiler
Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Lausanne, Switzerland
MIchel Aguet
Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, Lausanne, Switzerland
Konrad Basler
Department of Molecular Life Sciences, University of Zurich, Zürich, Switzerland
Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology; Faculty of Medicine and Health Sciences; Linköping University, Linköping, Sweden
BCL9 and PYGO are β-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of β-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the β-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a β-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/β-catenin-dependent transcriptional complex.
