The developmental factor TBX3 engages with the Wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes

• 成果类型: Article
• 署名作者: Jauregi-Miguel, Amaia; Soderholm, Simon; Weiss, Tamina; Nordin, Anna; Ghezzi, Valeria; Brutsch, Salome M.; Pagella, Pierfrancesco; van de Grift, Yorick; Zambanini, Gianluca; Ulisse, Jacopo; Mattia, Alessandro; Deviatiiarov, Ruslan; Faustini, Elena; Moparthi, Lavanya; Zhong, Wenjing; Bjornsson, Bergthor; Sandstrom, Per; Lundqvist, Erik; Lottersberger, Francisca; Koch, Stefan; Moor, Andreas E.; Sun, Xiao-Feng; von Castelmur, Eleonore; Sheng, Guojun; Cantu, Claudio
• 署名单位: Linkoping University; Linkoping University; Linkoping University; Linkoping University; Kazan Federal University; Russian Academy of Medical Sciences; Endocrinology Research Centre; Juntendo University; Linkoping University; Linkoping University; Linkoping University; Linkoping University; Linkoping University; Linkoping University; Kumamoto University; Max Planck Society
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12228
• DOI: 10.1073/pnas.2419691122
• 发表日期: 2025-05-13
• 关键词: beta-catenin; wnt; target; identification; proteins; domain; pluripotency; inhibition; survival; PATHWAY

摘要

Wnt signaling orchestrates gene expression in a plethora of processes during development and adult cell homeostasis via the action of nuclear beta-catenin. Yet, little is known about how beta-catenin generates context-specific transcriptional outcomes. Understanding this will reveal how aberrant Wnt/beta-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/beta-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/beta-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/beta-catenin in CRC, and its mechanism of action exposes protein-interaction surfaces as putative druggable targets.