ZFIN ID: ZDB-PUB-181005-4
CCAAT/enhancer-binding protein-β functions as a negative regulator of Wnt/β-catenin signaling through activation of AXIN1 gene expression
Park, S., Lee, M.S., Gwak, J., Choi, T.I., Lee, Y., Ju, B.G., Kim, C.H., Oh, S.
Date: 2018
Source: Cell Death & Disease   9: 1023 (Journal)
Registered Authors: Kim, Cheol-Hee, Lee, Mi-Sun
Keywords: none
MeSH Terms:
  • 3T3-L1 Cells
  • Animals
  • Axin Protein/metabolism*
  • CCAAT-Enhancer-Binding Protein-beta/metabolism*
  • Carcinoma, Hepatocellular/metabolism
  • Cell Line
  • Cell Proliferation/physiology
  • Down-Regulation/physiology
  • Drosophila
  • Gene Expression/physiology*
  • HEK293 Cells
  • Humans
  • Liver Neoplasms/metabolism
  • Mice
  • Signal Transduction/physiology*
  • Wnt Signaling Pathway/physiology*
  • Zebrafish
  • beta Catenin/metabolism*
PubMed: 30283086 Full text @ Cell Death Dis.
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.