USF1 Silencing Reduces Ferroptosis Resistance in Prostate Cancer Cells.

Background: Ferroptosis is an iron-dependent cell death mode. Ferroptosis resistance is related to prostate cancer (PCa) invasion; However, there is vague understanding with regard to the underlying mechanism. This study was undertaken to clarify the role and mechanism of upstream stimulatory factor 1 (USF1) in ferroptosis resistance in invasive PCa.

Methods: USF1 was silenced in the human PCa cell lines C4-2B and PC-3. After these cells were treated with a ferroptosis inhibitor, cell viability and invasion and the expression of glutathione peroxidase 4 (GPX4) were evaluated. Chromatin immunoprecipitation and Dual-luciferase reporter assay suggested an interaction between USF1 and brain-expressed X-linked protein 1 (BEX1). Consequently, BEX1 was overexpressed in USF1-silenced C4-2B and PC-3 cells and its effects on cell viability and invasion and GPX4 expression were examined.

Results: USF1 silencing mitigated PCa cell viability and invasion. Treatment with a ferroptosis inhibitor counteracted the inhibitory roles of USF1 silencing in cell invasion and GPX4 expression. Additionally, USF1 silencing decreased BEX1 expression and USF1 was found to bind to the BEX1 promoter. BEX1 overexpression reversed the influences of USF1 silencing on the viability, BEX1 protein expression, invasive ability and ferroptosis of PCa cells.

Conclusions: USF1 activates the transcription of BEX1, preventing PCa cell ferroptosis and promoting cell invasion. Therefore, USF1 silencing may inhibit the progression of PCa by reducing ferroptosis resistance.