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

作者：Ji Liu, Niraj Maskey, Xiaojun Zhu, Yadong Guo, Zhijin Zhang, Aimaitiaji Kadier, Zhuoran Gu, Hong Wang, Libin Zou, Chuanyong Guo, Bin Yang, Junfeng Zhang, Shiyu Mao, Xudong Yao · 发表于：Experimental & Molecular Medicine · 年份：2025 · DOI：10.1038/s12276-025-01540-y · 被引用次数：7 · 研究领域：Circular RNAs in diseases、RNA modifications and cancer、RNA Research and Splicing

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 overexpres...