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CREB stimulates GPX4 transcription to inhibit ferroptosis in lung adenocarcinoma
Open accessAbstract
Ferroptosis is a new form of regulated cell death and closely related to cancer. However, the mechanism underlying the regulation of ferroptosis in lung adenocarcinoma (LUAD) remains unclear. IB, IHC and ELISA were performed to analyze protein expression. RT‑qPCR was used to analyze mRNA expression. Cell viability, 3D cell growth, MDA, the generation of lipid ROS and the Fe2+ concentration were measured to evaluate the responses to the induction of ferroptosis. Measurement of luciferase activity and ChIP were used to analyze the promoter activity regulated by the transcriptional regulator. Co‑IP assays were performed to identify protein‑protein interactions. In the present study, it was revealed that cAMP response element‑binding protein (CREB) was highly expressed in LUAD, and knockdown of CREB inhibited cell viability and growth by promoting apoptosis‑ and ferroptosis‑like cell death, concurrently. It was observed that CREB suppressed lipid peroxidation by binding the promoter region of glutathione peroxidase 4 (GPX4), and this binding could be enhanced by E1A binding protein P300 (EP300). The bZIP domain in CREB and the CBP/p300‑HAT domain in EP300 were essential for CREB‑EP300 binding in LUAD cells. Finally, it was revealed that CREB, GPX4, EP300 and 4‑HNE were closely related to tumor size and stage, and tumors with a higher degree of malignancy were more likely to have a low degree of lipid peroxidation. Therefore, targeting this CREB/EP300/GPX4 axis may provide new strategies for treating LUAD.
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“Several transcription factors including AP-1 (60, 61), CREB (62, 63), ATF4 (64), and NRF2 (45, 65, 66) have been shown to regulate either directly or indirectly GPX4 levels in different cellular contexts.”
From Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis (2024) · cites this paper as [62]
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GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment
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Metadata
- Authors
- Wang, Z., Zhang, X., Tian, X., Yang, Y., Ma, L., Wang, J., & Yu, Y.
- Affiliations
- Shanghai University of Traditional Chinese Medicine (CN)
- Shanghai Jiao Tong University (CN)
- Tongji University (CN)
- Corresponding author
- Wang, Jiayi
- Yu, Yongchun
- Venue
- Oncology Reports
- Publisher
- Spandidos Publications
- Published
- 2021-04-02
- Volume
- 45
- Issue
- 6
- ISSN
- 1021-335X (ISSN-L)
- 1791-2431
- PMC
- PMC8042667
- OpenAlex
- W3146768338
- Cited by
- 122
- References
- 53
- Citations by year
- 2026: 14 · 2025: 16 · 2024: 34 · 2023: 25 · 2022: 22 · 2021: 11
- FWCI
- 15.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Oncology Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81871907, 81822029, 81902869, 81902315, 81774291, 81672332)
- Shanghai Education Development Foundation (18CG16)
- Shanghai Municipal Education Commission
- Shanghai Chest Hospital (2018YNJCQ06)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- CREB, GPX4, ferroptosis, lung adenocarcinoma, EP300, lipid peroxidation, transcriptional regulation, 4-hydroxynonenal, apoptosis, bZIP domain, protein-protein interaction, tumor malignancy
- MeSH terms
- Adenocarcinoma of Lung, Ferroptosis, Phospholipid Hydroperoxide Glutathione Peroxidase, Humans, Lung, Lung Neoplasms, Promoter Regions, Genetic, Protein Binding, Lipid Peroxidation, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Cyclic AMP Response Element-Binding Protein, Cell Line, Tumor, E1A-Associated p300 Protein, Gene Knockdown Techniques, HEK293 Cells, Datasets as Topic
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