The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells

Makoto Inoue; Yohei Uchida; Makoto Edagawa; Manabu Hirata; Jun Mitamura; Daiki Miyamoto; Kenji Taketani; Shigeki Sekine; Junya Kawauchi; Shigetaka Kitajima

doi:10.1371/journal.pone.0194160

The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells

PLoS One. 2018 Jul 2;13(7):e0194160. doi: 10.1371/journal.pone.0194160. eCollection 2018.

Authors

Affiliations

¹ Department of Biochemical Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
² Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
³ Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / genetics*
Biomarkers, Tumor / genetics*
Carcinogenesis / genetics*
Cell Movement / genetics
Cell Proliferation / genetics
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / pathology
Gene Expression Regulation, Neoplastic
HCT116 Cells
Humans
Matrix Metalloproteinase 2 / genetics
Matrix Metalloproteinase 9 / genetics
Neoplasm Invasiveness / genetics*
Neoplasm Invasiveness / pathology
Protein Binding
Tissue Inhibitor of Metalloproteinase-3 / genetics
Transcription Factor 4 / genetics
Wnt Signaling Pathway / genetics
beta Catenin / genetics

Substances

ATF3 protein, human
Activating Transcription Factor 3
Biomarkers, Tumor
CTNNB1 protein, human
TCF4 protein, human
TIMP3 protein, human
Tissue Inhibitor of Metalloproteinase-3
Transcription Factor 4
beta Catenin
MMP2 protein, human
Matrix Metalloproteinase 2
MMP9 protein, human
Matrix Metalloproteinase 9

Associated data

figshare/10.6084/m9.figshare.5996516

Grants and funding

This work was supported in part by Grants-in-Aids for Scientific Research 25134708 and 15K08300 to Shigetaka Kitajima from the Ministry of Education, Culture, Sports, Science and Technology, Japan.