2025-05-22 リンショーピング大学 (LiU)
<関連情報>
- https://liu.se/en/news-item/key-mechanism-in-embryo-development-makes-cancer-more-aggressive
- https://www.pnas.org/doi/10.1073/pnas.2419691122
大腸癌における発生因子TBX3はWnt/β-カテニン転写複合体と関与し転移遺伝子を制御する The developmental factor TBX3 engages with the Wnt/β-catenin transcriptional complex in colorectal cancer to regulate metastasis genes
Amaia Jauregi-Miguel, Simon Söderholm, Tamina Weiss, +21 , and Claudio Cantù
Proceedings of the National Academy of Sciences Published:May 9, 2025
DOI:https://doi.org/10.1073/pnas.2419691122
Significance
Dysregulated Wnt signaling is a well-established driver of colorectal carcinogenesis. However, its pivotal role in normal intestinal stem cell homeostasis has posed significant challenges for its therapeutic inhibition, highlighting the need for discovering cancer-specific mechanisms. Our research reveals that the transcription factor TBX3, long recognized for its role in limb and heart embryogenesis, becomes aberrantly present in colorectal cancers (CRC). In this extraneous context, TBX3 adopts new functions: Instead of binding the DNA as a classic transcription factor, it employs short, conserved motifs on its surface to stick to other protein complexes—including the Wnt machinery—and fosters metastasis-inducing genetic programs. We hypothesize that targeting TBX3 could impair this aberrant embryonic-like behavior without affecting adult homeostasis.
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.
