DDR1 Targeting HOXA6 Facilitates Bladder Cancer Progression via Inhibiting Ferroptosis

Abstract

Ferroptosis is an important factor affecting the progression of bladder cancer (BC). Previous studies have confirmed that discoidin domain receptor 1 (DDR1) promotes BC progression. However, the regulatory mechanisms of BC ferroptosis are largely unknown. Therefore, this study aimed to investigate the regulatory effects of DDR1 on BC cell ferroptosis. Ferroptosis-sensitive and -resistant BC cells were screened, and reverse-transcription quantitative PCR and western blotting were used to determine the expression of DDR1 in BC cells. In vitro and in vivo assays were performed to analyse the mechanisms of DDR1 in BC ferroptosis. The ferroptosis inducer erastin inhibited DDR1 expression in TCCSUP cells. The ferroptosis inhibitor ferrostatin-1 inhibited BC cell death caused by DDR1 knockdown. DDR1 increased glutathione, glutathione peroxidase 4 and solute carrier family 7 member 11 expression, while decreasing malondialdehyde and Fe²⁺ levels and acyl-CoA synthetase long-chain family member 4 levels and inhibiting epithelial mesenchymal transition and neurofibromin 2-yes-associated protein. These effects were abrogated by the knockdown of homeobox A6 (HOXA6). DDR1 targeting of HOXA6 facilitated BC growth and inhibited BC ferroptosis in vivo. DDR1 promotes BC progression by inhibiting ferroptosis and targeting HOXA6. Thus, DDR1 may serve as a potential therapeutic target for BC.

Keywords: DDR1; HOXA6; bladder cancer; ferroptosis; progression.