Phosphorylated ATF1 at Thr184 promotes metastasis and regulates MMP2 expression in gastric cancer
Open accessAbstract
Background: Studies have revealed an important role of activating transcription factor 1 (ATF1) and phosphorylated ATF1 at Ser63 in tumors. Our previous study identified Thr184 as a novel phosphorylation site of ATF1. However, the role of phosphorylated ATF1 at Thr184 (p-ATF1-T184) in tumor is unclear. This study figured out the role of p-ATF1-T184 in the metastasis of gastric cancer (GC) and in the regulation of Matrix metallopeptidase 2 (MMP2). Methods: Immunohistochemical analysis (IHC) was performed to analyze the level of p-ATF1-T184 and its relationship with clinicopathological characteristics. Wound scratch test, Transwell assay were used to observe the role of p-ATF1-T184 in the invasion and metastasis of GC. The regulation of MMP2 by p-ATF1-T184 was investigated by a series of experiments including quantitative RT-PCR, western blot, gelatin zymography assay, Chromatin immunoprecipitation (ChIP), luciferase reporter assay and cycloheximide experiment. The Cancer Genome Atlas (TCGA) data were used to analyze the expression and prognostic role of ATF1 and MMP2 in GC. Mass spectrometry (MS) following co-immunoprecipitation (co-IP) assay was performed to identify potential upstream kinases that would phosphorylate ATF1 at Thr184. Results: High expression level of p-ATF1-T184 was found and significantly associated with lymph node metastasis and poor survival in a GC cohort of 126 patients. P-ATF1-T184 promoted migration and invasion of gastric cancer cells. Phosphorylation of ATF1-T184 could regulate the mRNA, protein expression and extracellular activity of MMP2. P-ATF1-T184 further increased the DNA binding ability, transcription activity, and stabilized the protein expression of ATF1. Moreover, TCGA data and IHC results suggested that the mRNA level of ATF1 and MMP2, and protein level of p-ATF1-T184 and MMP2 could be prognosis markers of GC. Two protein kinase related genes, LRBA and S100A8, were identified to be correlated with the expression ATF1 in GC. Conclusion: Our results indicated that p-ATF1-T184 promoted metastasis of GC by regulating MMP2.
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ATF1 is known to influence the expression of matrix metalloproteinases across multiple diseases.
“The transcription factor ATF1 is known to influence the expression of matrix metalloproteinases across multiple diseases30,31.”
From ATF1 and miR-27b-3p drive intervertebral disc degeneration through the PPARG/NF-κB signaling axis (2025) · cites this paper as [31]
The Discussion reports that ATF1 increases MMP2 expression in lung cancer cells, and the Results show that phosphorylated ATF1 regulates MMP2 expression in gastric cancer cells. This supports an effect across more than one cancer, but the paper addresses only MMP2, not matrix metalloproteinases more broadly. (LLM, conf=0.85)
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Self-citation
- Authors
- Li, T., Cao, H., Wu, S., Zhong, P., Ding, J., Wang, J., Wang, F., He, Z., & Huang, G.-L.
- Affiliations
- Guangdong Medical College (CN)
- Corresponding author
- He, Zhiwei
- Venue
- Journal of Translational Medicine
- Published
- 2022-04-09
- Volume
- 20
- Issue
- 1
- Pages
- 169-169
- ISSN
- 1479-5876 (ISSN-L)
- PMC
- PMC8994398
- OpenAlex
- W4223639868
- Cited by
- 16
- References
- 41
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 3
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Translational Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (No:81772982)
- the Special Innovation Fund of Department of Education of Guangdong Province (No:2019KTSCX049)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- gastric cancer, metastasis, MMP-2, cell invasion, cell migration, lymph node metastasis, prognostic factors, LRBA, S100A8, protein kinases, transcriptional regulation, protein stability, DNA-binding activity, prognostic genes
- MeSH terms
- Cell Movement, Humans, Prognosis, RNA, Messenger, Stomach Neoplasms, Gene Expression Regulation, Neoplastic, Matrix Metalloproteinase 2, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Activating Transcription Factor 1
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