Journal Article10.1101/2023.12.18.571901
The Developmental Transcription Factor TBX3 Physically Engages with the Wnt/β-catenin Transcriptional Complex in Human Colorectal Cancer Cells to Regulate Metastasis Genes
Amaia Jauregi-Miguel,Simon Söderholm,Tamina Weiss,Anna Nordin,Valeria Ghezzi,Salome Brütsch,Pierfrancesco Pagella,Yorick Bernardus Cornelis van de Grift,Gianluca Zambanini,Jacopo Ulisse,Alessandro Mattia,Ruslan Deviatiiarov,Elena Faustini,Lavanya Moparthi,Francisca Lottersberger,Stefan Koch,Andreas E. Moor,Xiao-Feng Sun,Eleonore von Castelmur,Guojun Sheng,Claudio Cantù +20 more
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TL;DR: TBX3 emerges as a key modulator of the oncogenic activity of Wnt/β-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface.
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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 β-catenin. Furthermore, neoplasia of the colorectal epithelium begins with aberrant Wnt/β-catenin signaling. Yet, little is known about how β-catenin generates context-specific transcriptional outcomes. We have previously identified the developmental 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 present and functionally active in human colorectal cancers. TBX3’s genomic binding pattern suggests a regulatory role that broadly coincides with that of Wnt/β-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/β-catenin in colorectal cancer, and its mechanism of action exposes a novel druggable protein-interaction surface.
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Citations
Exhaustive identification of genome-wide binding events of transcriptional regulators
Anna Nordin,Pierfrancesco Pagella,Gianluca Zambanini,Claudio Cantù +3 more
TL;DR: ICEBERG is a novel approach to identify the complete binding events of transcriptional regulators, uncovering rare and dynamic regulation events.
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Exhaustive identification of genome-wide binding events of transcriptional regulators with ICEBERG
TL;DR: In this paper , an experimental and analytical pipeline that harnesses large numbers of CUT&RUN replicates to discover the full set of binding events and chart the line between false positives and false negatives is presented.
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