Abstract

Aberrant Wnt signalling promotes oncogenesis by increasing the nuclear accumulation of β-catenin to activate downstream target genes. However, the mechanism of β-catenin recruitment to the Wnt target-gene promoter, a critical step for removing the co-repressor complex, is largely unknown. Here, we report that transducin β-like protein 1 (TBL1) and its highly related family member TBLR1 were required for Wnt–β-catenin-mediated transcription. Wnt signalling induced the interaction between β-catenin and TBL1–TBLR1, as well as their binding to Wnt target genes. Importantly, the recruitment of TBL1–TBLR1 and β-catenin to Wnt target-gene promoters was mutually dependent on each other. Furthermore, the depletion of TBL1–TBLR1 significantly inhibited Wnt–β-catenin-induced gene expression and oncogenic growth in vitro and in vivo. Our results unravel two new components required for nuclear β-catenin function, and have important implications in developing new strategies for inhibiting Wnt–β-catenin-mediated tumorigenesis.