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

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

SUBMITTER: Park S 

PROVIDER: S-EPMC6170413 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature