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

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.

Phosphorylation inhibition of protein-tyrosine phosphatase 1B tyrosine-152 induces bone regeneration coupled with angiogenesis for bone tissue engineering

“…It has been reported that the overexpression of Runx2 in osteoblasts downregulates the activity of the ATF3 promoter, suggesting that ATF3 may be a downstream factor of Runx2 [ 52 ]. ATF3 is transcriptionally activated by the binding of β-catenin and TCF4 to the redundant TCF4 site in the proximal promoter region of the ATF3 gene, indicating that ATF3 is a direct target of the β-catenin pathway [ 54 ]. In vivo experiments also confirmed that 152RM promoted the formation and mineralization of new bone in the bone defects of DBM-MSN/152RM scaffolds.…”

MAPK signaling links the injury response to Wnt-regulated patterning inHydraregeneration

“…Whereas the Wnt9/10c promotor had higher probability scores for ATF and ATF2/CREB, which act as activating transcription factors, the promotors of Wnt3 and Wnt7 had a higher binding probability for ATF3, which is known to act as a repressor (Fig. 6D) (Hai, 2006;Hai et al, 1999;Inoue et al, 2018;Katoh, 2018;Zhou et al, 2017). Interestingly, one consensus sequence of ATF3 was further predicted to be located in the repressor element of Hydra Wnt3 (Nakamura et al, 2011).…”

Activating transcription factor 3 inhibits endometrial carcinoma aggressiveness via JunB suppression

“…MMPs and TIMPs have prominent roles in cancer invasion and metastasis. TIMPs, binding to MMPs at a 1:1 molar ratio, are able to block the access of substrates to the catalytic domain of endopeptidases and eventually inhibit the bioactivities of MMPs ( 20 ). Furthermore, increases in the MMP/TIMP ratio have been reported to affect invasion and metastasis, and are widely considered as a marker for cancer invasion ( 21 - 23 ).…”