The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

Jauregi-Miguel, A.; Soderholm, S.; Weiss, T. L.; Nordin, A.; Ghezzi, V.; Bruetsch, S. M.; Pagella, P.; van de Grift, Y.; Zambanini, G.; Ulisse, J.; Mattias, A.; Deviatiiarov, R.; Faustini, E.; Moparthi, L.; Lottersberger, F.; Koch, S.; Moor, A. E.; Sun, X.-F.; von Castelmur, E.; Sheng, G.; Cantu', C.

doi:10.1101/2023.12.18.571901

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bioRxiv · 10.1101/2023.12.18.571901

The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes

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Abstract

Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear {beta}-catenin. Furthermore, neoplasia of the colorectal epithelium begins with aberrant Wnt/{beta}-catenin signaling. Yet, little is known about how {beta}-catenin generates context-specific transcriptional outcomes. We have previously identified the developmental transcription factor TBX3 as a tissue-specific component of the Wnt/{beta}-catenin nuclear complex during mouse forelimb development. In this study, we show that TBX3 is present and functionally active in human colorectal cancers. TBX3s genomic binding pattern suggests a regulatory role that broadly coincides with that of Wnt/{beta}-catenin. Moreover, proteomics proximity labelling indicated that, during Wnt pathway activation, TBX3 is vicinal to several protein partners, including the transcription factors TCF/LEF and chromatin remodeling complexes which are usually found at Wnt responsive elements. Sequence and structure analysis revealed that TBX3 possesses an exposed Asp-Pro-Phe (NPF) motif predicted by AlphaFold2 Multimer to mediate direct interactions with several Wnt-activated TBX3 partners. Deletion of NPF abrogates TBX3 proximity to these partners and its ability to modulate Wnt-dependent transcription. TBX3 emerges as a key modulator of the oncogenic activity of Wnt/{beta}-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface.

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Jauregi-Miguel, A., Soderholm, S., Weiss, T. L., Nordin, A., Ghezzi, V., Bruetsch, S. M., Pagella, P., van de Grift, Y., Zambanini, G., Ulisse, J., Mattias, A., Deviatiiarov, R., Faustini, E., Moparthi, L., Lottersberger, F., Koch, S., Moor, A. E., Sun, X.-F., von Castelmur, E., Sheng, G., Cantu', C.. 2023-12-19. The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes. https://doi.org/10.1101/2023.12.18.571901

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