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

초록

Axin1, a concentration-limiting component of the beta-catenin destruction complex, negatively regulates the Wnt/beta-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-beta (C/EBP-beta) activates axis inhibition protein 1 (AXIN1) gene expression, thereby attenuating Wnt/beta-catenin signaling. C/EBP-beta interacted with cis-regulatory element for C/EBP-beta 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-beta negatively regulates the Wnt/beta-catenin pathway. Small-molecule-based up-regulation of C/EBP-beta induces AXIN1 gene expression and down-regulates the intracellular beta-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/beta-catenin signaling.

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