Abstract
Aberrant Wnt/β-catenin signaling is implicated in tumorigenesis and the progression of human colorectal cancers, and mutations in the components of the Wnt/β-catenin signaling pathway are observed in the majority of patients. Therefore, extensive studies on the Wnt signaling pathway and its target genes are crucial to understand the molecular events of tumorigenesis and develop an efficacious therapy. In this study, we showed that the stress response gene ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site at the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the Wnt/β-catenin pathway. The loss of function or overexpression studies showed that ATF3 inhibited the migration or invasion of HCT116 cells. The expression of some MMP and TIMP genes and the ratio of MMP2/9 to TIMP3/4 mRNAs was differentially regulated by ATF3. Therefore, though ATF3 is activated downstream of the Wnt/β-catenin pathway, it acts as a negative regulator of the migration and invasion of HCT116 human colon cancer cells exhibiting aberrant Wnt/β-catenin activity. ATF3 is a candidate biomarker and target for human colorectal cancer treatment and prevention.
Highlights
The Wnt signaling pathway, which is conserved in various species, determines cell fate and tissue development [1]
To address whether the activating transcription factor 3 (ATF3) gene is regulated by the Wnt signaling pathway in human colon cancer cells, the ATF3 protein expression level was determined in several human colon cancer cell lines with adenomatous polyposis coli (APC) or β-catenin mutations (S1 Fig)
We identified a TCF4 binding element at the -34 to -28 region of the ATF3 gene promoter, and this was supported by the results of the Chromatin immunoprecipitation (ChIP) and DNA affinity precipitation (DNAP) assays (Fig 3)
Summary
The Wnt signaling pathway, which is conserved in various species, determines cell fate and tissue development [1]. It consists of two different major pathways, namely, the canonical and the non-canonical pathways [2]. The activation of the canonical Wnt signaling pathway is triggered by the binding of Wnt molecules to the Frizzled receptors (Fz) [3] and LDL-receptor related protein-5/6 co-receptor (LRP5/6) [4]. This leads to the inhibition of glycogen synthase kinase-3β (GSK-3β) and proteasome-dependent degradation of β-catenin [5]. The stabilized βcatenin forms a complex with the T-cell specific transcription factor/lymphoid enhancer-
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
