CCAAT/enhancer-binding protein-β functions as a negative regulator of Wnt/β-catenin signaling through activation of AXIN1 gene expression.

Axin1, a concentration-limiting component of the β-catenin destruction complex, negatively regulates the Wnt/β-catenin pathway. Axin1 concentration is reported to be regulated by proteasomal degradation; however, its transcriptional regulation has not yet been reported. Here, we demonstrated that CCAAT/enhancer-binding protein-β (C/EBP-β) activates axis inhibition protein 1 (AXIN1) gene expression, thereby attenuating Wnt/β-catenin signaling. C/EBP-β interacted with cis-regulatory element for C/EBP-β in the 5'-upstream sequences of the AXIN1 gene and increased AXIN1 promoter activity. Functional analysis using Drosophila and zebrafish models established that C/EBP-β negatively regulates the Wnt/β-catenin pathway. Small-molecule-based up-regulation of C/EBP-β induces AXIN1 gene expression and down-regulates the intracellular β-catenin level, thereby inhibiting hepatoma cell growth. Thus, our findings provide a unique mechanistic insight into the regulation of Axin homeostasis and present a novel strategy for the development of anticancer therapeutics targeting Wnt/β-catenin signaling.