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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

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

Park Seoyoung S Lee Mi-Sun MS Gwak Jungsug J Choi Tae-Ik TI Lee Youngseok Y Ju Bong Gun BG Kim Cheol-Hee CH Oh Sangtaek S

Cell death & disease 20181003 10

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/ ...[more]

PMID: 30283086

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Project description:Colorectal cancer exhibits aberrant activation of Wnt/β-catenin signaling. Many inhibitors of the Wnt/β-catenin pathway have been tested for Wnt-dependent cancers including colorectal cancer, but are unsuccessful due to severe adverse reactions. FL3 is a synthetic derivative of natural products called flavaglines, which exhibit anti-inflammatory and cytoprotective properties in intestinal epithelial cells, but has not been previously tested in cell or preclinical models of intestinal tumorigenesis. In vitro studies suggest that flavaglines target prohibitin 1 (PHB1) as a ligand, but this has not been established in the intestine. PHB1 is a highly conserved protein with diverse functions that depend on its posttranslational modifications and subcellular localization. Here, we demonstrate that FL3 combats intestinal tumorigenesis in the azoxymethane-dextran sodium sulfate and ApcMin/+ mouse models and in human colorectal cancer tumor organoids (tumoroids) by inhibiting Wnt/β-catenin signaling via induction of Axin1 expression. FL3 exhibited no change in cell viability in normal intestinal epithelial cells or human matched-normal colonoids. FL3 response was diminished in colorectal cancer cell lines and human colorectal cancer tumoroids harboring a mutation at S45 of β-catenin. PHB1 deficiency in mice or in human colorectal cancer tumoroids abolished FL3-induced expression of Axin1 and drove tumoroid death. In colorectal cancer cells, FL3 treatment blocked phosphorylation of PHB1 at Thr258, resulting in its nuclear translocation and binding to the Axin1 promoter. These results suggest that FL3 inhibits Wnt/β-catenin signaling via PHB1-dependent activation of Axin1. FL3, therefore, represents a novel compound that combats Wnt pathway-dependent cancers, such as colorectal cancer. SIGNIFICANCE: Targeting of PHB1 by FL3 provides a novel mechanism to combat Wnt-driven cancers, with limited intestinal toxicity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/17/3519/F1.large.jpg.

Dataset Information

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

Publications

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

Similar Datasets

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