TBX3 acts as tissue-specific component of the Wnt/β-catenin transcriptional complex

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...

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Bibliographic Details
Published in:eLife 2020-08, Vol.9
Main Authors: Zimmerli, Dario, Borrelli, Costanza, Jauregi-Miguel, Amaia, Söderholm, Simon, Brütsch, Salome, Doumpas, Nikolaos, Reichmuth, Jan, Murphy-Seiler, Fabienne, Aguet, MIchel, Basler, Konrad, Moor, Andreas E, Cantù, Claudio
Format: Article
Language:English
Subjects:
Animals
Cancer
Cofactors
Colon
Colorectal cancer
Colorectal carcinoma
development
Developmental Biology
Drinking water
Female
Gene expression
gene regulation
Genetic analysis
Genomes
HCT116 Cells
Humans
Intestine
LEF protein
limb development
Male
Metastases
Mice
Mutation
Organ Specificity
Proteins
Regulatory sequences
Short Report
Small intestine
Stem cells
T-Box Domain Proteins - genetics
T-Box Domain Proteins - metabolism
transcription
Transcription Factors - genetics
Transcription Factors - metabolism
Tumor Cells, Cultured
Tumors
Wnt protein
Wnt Signaling Pathway
wnt signalling
Zebrafish
β-Catenin
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Summary: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 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.58123