Hepatic nuclear factor 4 alpha promotes the ferroptosis of lung adenocarcinoma via transcriptional activation of cytochrome P450 oxidoreductase

PeerJ

article

Valeria Besskaya¹  Huan Zhang¹  Yunyi Bian¹  Jiaqi Liang¹  Guoshu Bi¹  Guangyao Shan¹  Cheng Zhan¹  Zongwu Lin¹ 

[1] Department of Thoracic Surgery, Zhongshan Hospital, Fudan University

关键词: Lung adenocarcinoma;    Ferroptosis;    HNF4A;    POR;    Transcript factor;   

DOI  :  10.7717/peerj.15377

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

Background Lung adenocarcinoma is one of the most prevalent cancers while ferroptosis is crucial for cancer therapies. This study aims to investigate the function and mechanism of hepatic nuclear factor 4 alpha (HNF4A) in lung adenocarcinomas’ ferroptosis. Materials and Methods HNF4A expression in ferroptotic A549 cells was detected. Then HNF4A was knocked down in A549 cells while overexpressed in H23 cells. Cells with changed HNF4A expression were tested for cytotoxicity and the level of cellular lipid peroxidation. The expression of cytochrome P450 oxidoreductase (POR) expression was examined after HNF4A was knocked down or overexpressed. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) and dual-luciferase assays were performed to validate the regulation of HNF4A on POR. Finally, POR was restored in HNF4A-altered cells to check whether it restores the effect of HNF4A on ferroptosis. Results We found that HNF4A expression significantly decreased in the ferroptosis of A549 cells, and this change can be blocked by deferoxamine, an inhibitor of ferroptosis. Knockdown of HNF4A inhibited ferroptosis in A549 cells while overexpression of HNF4A promoted ferroptosis in H23 cells. We identified a key ferroptosis-related gene, POR serves as a potential target gene of HNF4A, whose expression was significantly changed in lung adenocarcinoma cells knocking down or overexpressing HNF4A. We demonstrated that HNF4A was bound to the POR’s promoter to enhance POR expression, and identified the binding sites via ChIP-qPCR and luciferase assays. Restoration of POR expression blocked the promoting effect of HNF4A on ferroptosis in lung adenocarcinoma. Conclusion HNF4A promotes POR expression through binding to the POR’s promoter, and subsequently promotes the ferroptosis of lung adenocarcinoma.

【 授权许可】

CC BY