Previous studies have demonstrated that circST6GALNAC6 is a tumor suppressor in bladder cancer. However, the role of circST6GALNAC6 in ferroptosis remains unclear. In the current study, ferroptosis was induced in bladder cancer cells by erastin. Functional experiments showed that overexpression of circST6GALNAC6 promoted ferroptosis of bladder cancer cells in vitro and in vivo. Mechanistic studies revealed that circST6GALNAC6 bound to the N-terminus of small heat shock protein 1 (HSPB1) and thus blocked the erastin-induced phosphorylation of HSPB1 at the Ser-15 site, a phosphorylation site in the protective response to ferroptosis stress. In addition, protein kinase C inhibited circST6GALNAC6-induced ferroptosis by increasing the overall phosphorylation level of HSPB1, further demonstrating the role of phosphorylation activation of HSPB1 in resistance to ferroptosis. Finally, the involvement of the HSPB1/p38 MAPK pathway in the downstream signal transduction of circST6GALNAC6 in bladder cancer ferroptosis regulation was determined. The regulatory mechanism of ferroptosis sensitivity dependent on circST6GALNAC6 expression levels in bladder cancer was revealed as circRNA regulation of various protein functions. CircST6GALNAC6 inhibits HSPB1 and promotes cell ferroptosis by occupying the phosphorylation site (Ser-15) of HSBP1 and activating the P38 MAPK signaling pathway. Therefore, enhancing the expression of circST6GALNAC6 to promote ferroptosis or using circST6GALNAC6 as a biomarker of ferroptosis sensitivity is of considerable importance to the development and application of ferroptosis intervention methods in bladder cancer.
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This work was supported by Hunan Provincial Natural Science Foundation of China (No. 2019JJ40442), National Natural Science Foundation of China (Grant no. 81972195), Hunan Provincial Key Area R&D Program (Grant no. 2019SK2253), Scientific Research Program of Hunan Provincial Health Commission (Grant no. 20201047) and Clinical Medical Technology Innovation Guide Project of Hunan Province (grant number S2020SFYLJS0311).
The authors declare no competing interests.
Ethics approval and consent to participate
Nude mice (male, 7–8 weeks old) were provided by Hunan SJA Laboratory Animal Co., Ltd, animal experiments were performed in accordance with the guidelines of the Committee on the Ethics of Animal Experiments of Central South University.
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Wang, L., Wu, S., He, H. et al. CircRNA-ST6GALNAC6 increases the sensitivity of bladder cancer cells to erastin-induced ferroptosis by regulating the HSPB1/P38 axis. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00826-3