CircCNOT6L modulates alternative splicing of SLC7A11 via splicing factor SRSF2 to confer ferroptosis resistance and promote metastasis in prostate cancer.

Prostate cancer (PCa) metastasis has emerged as a leading cause of mortality globally. Owing to the distinctive looping structure, circular RNA has become an ideal biological tumor marker. Here we investigate the mechanism and function of circular RNA, specifically circCNOT6L, on PCa metastasis. A loss-of-function assay was conducted in vitro to assess the impact of circCNOT6L on cancer cell proliferation, migration, invasion and ferroptosis. In addition, a xenograft mouse model was used to elucidate the influence of circCNOT6L on subcutaneous tumor xenograft and lung metastasis. Biochemical experiments elucidated the molecular mechanism by which circCNOT6L promotes malignant progression in PCa cells by modulating ferroptosis. Moreover, the combination of circCNOT6L-si and a ferroptosis activator was tested in organoids to evaluate their potential as suppressors of tumorigenesis. The novel circular RNA, circCNOT6L, was highly expressed in both PCa metastatic tissues and cells. circCNOT6L suppression resulted in a notable inhibition in PCa cell migration, invasion and ferroptosis in vitro. Furthermore, circCNOT6L inhibition hindered the growth and metastasis of mouse xenografts. Mechanistically, circCNOT6L, generated by the RNA-binding protein EIF4A3, competes with miR-143-5p for binding, thereby facilitating SRSF2-dependent splicing of SLC7A11 precursor RNA. This process inhibited ferroptosis in PCa cells and promoted PCa progression. Finally, inhibiting circCNOT6L overexpression in combination with the ferroptosis activator (erastin) significantly suppressed the viability of PCa-derived organoids. In conclusion, in the present study, we found that circCNOT6L induced by EIF4A3 through the SRSF2-SLC7A11 axis effectively inhibits ferroptosis, which in turn promotes malignant progression of PCa.