Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410013, Hunan, PR China.
Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410013, Hunan, PR China.
Lab Invest. 2022 Dec;102(12):1323-1334. doi: 10.1038/s41374-022-00826-3. Epub 2022 Aug 9.
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.
先前的研究表明 circST6GALNAC6 是膀胱癌的肿瘤抑制因子。然而，circST6GALNAC6 在铁死亡中的作用尚不清楚。在本研究中，用 erastin 诱导膀胱癌细胞发生铁死亡。功能实验表明，circST6GALNAC6 的过表达促进了膀胱癌细胞在体外和体内的铁死亡。机制研究表明，circST6GALNAC6 与小热休克蛋白 1（HSPB1）的 N 端结合，从而阻止 erastin 诱导的 HSPB1 在丝氨酸 15 位的磷酸化，该磷酸化是铁死亡应激保护性反应的一个磷酸化位点。此外，蛋白激酶 C 通过增加 HSPB1 的整体磷酸化水平来抑制 circST6GALNAC6 诱导的铁死亡，进一步证明了 HSPB1 磷酸化激活在抵抗铁死亡中的作用。最后，确定了 HSPB1/p38 MAPK 途径在 circST6GALNAC6 调控膀胱癌铁死亡下游信号转导中的作用。揭示了依赖于 circST6GALNAC6 在膀胱癌中表达水平的铁死亡敏感性的调控机制是 circRNA 对各种蛋白质功能的调控。circST6GALNAC6 通过占据 HSPB1 的磷酸化位点（Ser-15）并激活 P38 MAPK 信号通路来抑制 HSPB1 并促进细胞铁死亡。因此，增强 circST6GALNAC6 的表达以促进铁死亡或使用 circST6GALNAC6 作为铁死亡敏感性的生物标志物，对铁死亡干预方法在膀胱癌中的开发和应用具有重要意义。
