TCF/LEF-mediated transcriptional regulation in the canonical Wnt pathway

The canonical Wnt signaling pathway is an evolutionarily conserved pathway that regulates embryonic development, tissue homeostasis, and stem cell maintenance. Central to this pathway, T-cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors interact with β-catenin and various co-regulators to form the multiprotein Wnt enhanceosome and mediate Wnt target gene expression. The specificity and intensity of the Wnt transcriptional response are finely tuned by co-repressor interactions, chromatin remodeling factors, and post-translational modifications. Isoform diversity among TCF/LEF family members further modulates their affinity for co-repressors and their susceptibility to regulatory modifications, contributing to distinct transcriptional outcomes. Dysregulation of TCF/LEF-mediated transcription has been implicated in disease pathogenesis, making it a critical therapeutic target. Recent advances have uncovered regulatory elements of the Wnt enhanceosome and opened new avenues for the development of small-molecule inhibitors targeting TCF/LEF-associated factors in Wnt-driven diseases. This review provides a comprehensive overview of TCF/LEF structure, isoform diversity, transcriptional regulation, and co-regulatory interactions, focusing on the molecular mechanisms governing TCF/LEF-mediated transcription in the canonical Wnt pathway. Furthermore, we discuss current drug discovery efforts aimed at modulating Wnt signaling for therapeutic applications.