Receptor accessory protein 6, a novel ferroptosis suppressor, drives oral squamous cell carcinoma by maintaining endoplasmic reticulum hemostasis

Abstract

Increasing evidence suggests a close association between endoplasmic-reticulum (ER) stress and ferroptosis. Receptor accessory protein 6 (REEP6) is known to play a crucial role in maintaining ER homeostasis. However, its involvement in ferroptosis remains unknown. In this study, we found that REEP6 was overexpressed, and its overexpression showed a significant association with tumor size and poor survival in OSCC patients. Besides, in vitro and in vivo assays together showed that REEP6 plays an oncogenic role in OSCC progression. The GO/KEGG, and GSEA analysis showed that REEP6 overexpression leads to the inactivation of ferroptosis signaling in OSCC. Moreover, REEP6 overexpression conferred resistance to RSL3, a ferroptosis inducer, whereas REEP6 knockdown sensitized OSCC cells to RSL3. Overexpression of REEP6 decrease the accumulation of iron ions, ROS production, but increase the number of mitochondrial cristae in OSCC cells. More importantly, we confirmed that REEP6 inhibited ferroptosis in OSCC cells by maintaining ER homeostasis via regulating ACSL4 expression. In addition, we identified promoter DNA hypomethylation as the underlying cause of REEP6 overexpression in OSCC. Taken together, REEP6 acts as a novel suppressor of ferroptosis, with its overexpression driven by promoter hypomethylation contributing to OSCC progression by ER stress-mediated ferroptosis via ACSL4.

Keywords: ACSL4; Endoplasmic-reticulum homeostasis; Ferroptosis; Oral squamous cell carcinoma; REEP6.