LEF1 enhances β-catenin transactivation through IDR-dependent liquid-liquid phase separation

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Wnt/β-catenin signaling is vital for cancer progression.
• This pathway is activated when β-catenin forms a transcription complex with LEF/TCF proteins in the nucleus.
• This complex initiates the transcription of Wnt target genes, driving cellular processes.

Purpose of the Study:

• To investigate the role of LEF1, a LEF/TCF family member, in Wnt/β-catenin signaling.
• To explore the formation of protein-protein interactions and their impact on gene transcription.
• To identify potential new therapeutic targets for cancer treatment.

Main Methods:

• In vivo and in vitro studies to observe LEF1 and β-catenin interactions.
• Analysis of intrinsically disordered regions (IDRs) in LEF1 function.
• Assessing the impact of disrupted LEF1 IDR on tumor proliferation and metastasis.
• Restoration of function studies using FUS IDR.

Main Results:

• LEF1 forms intrinsically disordered region (IDR)-dependent condensates with β-catenin.
• These condensates are essential for β-catenin-dependent transcription.
• Disruption of LEF1's IDR abrogated its tumor-promoting activity.
• Replacing the disrupted LEF1 IDR with FUS IDR restored the promoting activity.

Conclusions:

• Liquid-liquid phase separation mediated by LEF1's IDR is critical for Wnt/β-catenin signaling.
• LEF1-β-catenin condensate formation is a key mechanism in cancer development.
• Targeting LEF1's IDR and its phase separation properties presents a novel therapeutic strategy for cancer.