The developmental factor TBX3 engages with the Wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes
Abstract
Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear β-catenin. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. Understanding this will reveal how aberrant Wnt/β-catenin signaling causes neoplasia specifically of the colorectal epithelium. We have previously identified the transcription factor TBX3 as a tissue-specific component of the Wnt/β-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is functionally active in human colorectal cancer (CRC). Here, genome-wide binding and transcriptomics analyses reveal that TBX3 regulates cancer metastasis genes in cooperation with Wnt/β-catenin. Proteomics proximity labeling performed across Wnt pathway activation shows that TBX3 engages with several transcription factors and chromatin remodeling complexes found at Wnt responsive elements (WRE). Protein sequence and structure analysis of TBX3 revealed short motifs, including an exposed Asn-Pro-Phe (NPF), that mediate these interactions. Deletion of these motifs abrogates TBX3’s proximity to its protein partners and its ability to enhance the Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in CRC, and its mechanism of action exposes protein-interaction surfaces as putative druggable targets.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Amaia Jauregi-Miguel
Wallenberg Centre for Molecular Medicine, Linköping University
Simon Söderholm
Wallenberg Centre for Molecular Medicine, Linköping University
Tamina Weiss
Wallenberg Centre for Molecular Medicine, Linköping University
Anna Nordin
Wallenberg Centre for Molecular Medicine, Linköping University
Valeria Ghezzi
Wallenberg Centre for Molecular Medicine, Linköping University
Salome M. Brütsch
Wallenberg Centre for Molecular Medicine, Linköping University
Pierfrancesco Pagella
Wallenberg Centre for Molecular Medicine, Linköping University
Yorick van de Grift
Wallenberg Centre for Molecular Medicine, Linköping University
Gianluca Zambanini
Wallenberg Centre for Molecular Medicine, Linköping University
Jacopo Ulisse
Wallenberg Centre for Molecular Medicine, Linköping University
Alessandro Mattia
Wallenberg Centre for Molecular Medicine, Linköping University
Ruslan Deviatiiarov
Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University
Elena Faustini
Wallenberg Centre for Molecular Medicine, Linköping University
Lavanya Moparthi
Wenjing Zhong
Wallenberg Centre for Molecular Medicine, Linköping University
Bergthor Björnsson
Department of Surgery in Linköping, Linköping University
Per Sandström
Department of Surgery in Linköping, Linköping University
Erik Lundqvist
Department of Biomedicine and Clinical Sciences, Linköping University
Francisca Lottersberger
Stefan Koch
Andreas E. Moor
Department of Biosystems Science and Engineering, Federal Institute of Technology Zürich
Xiao-Feng Sun
Department of Oncology, Division of Surgery, Orthopedics and Oncology, Faculty of Medicine and Health Sciences, Linköping University
Eleonore von Castelmur
Wallenberg Centre for Molecular Medicine, Linköping University
Guojun Sheng
Claudio Cantù
Wallenberg Centre for Molecular Medicine, Linköping University