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

Area of Science:

• Molecular Biology
• Cancer Research
• Genetics

Background:

• Wnt/β-catenin signaling is crucial for development and homeostasis, but its aberrant activation drives colorectal cancer (CRC).
• The precise mechanisms by which nuclear β-catenin achieves context-specific gene regulation remain unclear.
• Transcription factor TBX3 was previously identified in mouse development and is investigated here for its role in CRC.

Purpose of the Study:

• To investigate the function of TBX3 in human colorectal cancer (CRC).
• To elucidate how TBX3 interacts with the Wnt/β-catenin pathway to regulate cancer-associated genes.
• To identify potential therapeutic targets within TBX3's interaction mechanisms.

Main Methods:

• Genome-wide binding and transcriptomics analyses to identify TBX3-regulated genes.
• Proteomics proximity labeling to map TBX3 protein interactions under Wnt pathway activation.
• Protein sequence and structure analysis to identify functional motifs in TBX3.

Main Results:

• TBX3 was found to be functionally active in human CRC, regulating cancer metastasis genes in conjunction with Wnt/β-catenin.
• TBX3 interacts with multiple transcription factors and chromatin remodelers at Wnt-responsive elements.
• Specific motifs in TBX3, including Asn-Pro-Phe (NPF), mediate these interactions and are essential for Wnt-dependent transcription.

Conclusions:

• TBX3 is a critical modulator of Wnt/β-catenin oncogenic activity in CRC.
• TBX3's mechanism involves protein-protein interactions mediated by specific motifs.
• These interaction surfaces represent potential druggable targets for CRC therapy.