SOX4 inhibits ferroptosis and promotes proliferation of endometrial cancer cells via the p53/SLC7A11 signaling

Abstract Aim Sex‐determining region Y‐related high‐mobility group box 4 (SOX4) has been reported to play a carcinogenic role in endometrial cancer (EC). However, the biological function and regulatory mechanisms of SOX4 in ferroptosis during the progression of EC are still unknown. Methods The mRNA and protein levels were scrutinized by quantitative reverse‐transcription polymerase chain reaction and western blot, respectively. The cell viability and proliferative capability were determined by cell counting kit‐8 assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) assay. Transcriptional regulation of gene expression was investigated by dual‐luciferase reporter assay and chromatin immunoprecipitation. Ferroptosis was evaluated by detection of reactive oxygen species, malondialdehyde, Fe 2+ , and ferroptosis‐related proteins. The mice test was implemented to confirm the influence of SOX4 on EC tumor growth and ferroptosis in vivo. Results We here discovered the elevation of SOX4 in EC tissues and cells. Functionally, SOX4 knockdown hampered proliferation and promoted ferroptosis of EC cells. Mechanistically, SOX4 bound to p53 promoter and inhibited its transcriptional activity in EC cells. In addition, p53 transcriptionally suppressed SLC7A11 expression in EC cells. Downregulation of p53 reverses the effect of SOX4 knockdown on proliferation and ferroptosis of EC cells. Finally, in vivo experiments demonstrated that SOX4 depletion hindered tumor growth and triggered ferroptosis in EC. Conclusions These findings collectively suggested that SOX4 inhibited ferroptosis and promoted proliferation of EC cells via the p53/SLC7A11 signaling. Our research unveiled a novel regulatory mechanism of ferroptosis in EC, offering promising perspectives for the development of EC therapies.