CREB stimulates GPX4 transcription to inhibit ferroptosis in lung adenocarcinoma

Wang,Zhixian; Zhang,Xiao; Tian,Xiaoting; Yang,Yueyue; Ma,Lifang; Wang,Jiayi; Yu,Yongchun

doi:10.3892/or.2021.8039

CREB stimulates GPX4 transcription to inhibit ferroptosis in lung adenocarcinoma

Authors:
- Zhixian Wang
- Xiao Zhang
- Xiaoting Tian
- Yueyue Yang
- Lifang Ma
- Jiayi Wang
- Yongchun Yu
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Affiliations: Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China, Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, P.R. China, Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai 200072, P.R. China
Published online on: April 2, 2021 https://doi.org/10.3892/or.2021.8039
Article Number: 88
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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