RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11
RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11
复制标题
RBMS1 通过 SLC7A11 的翻译控制来调节肺癌铁死亡。
DOI：
10.1172/jci152067
复制
发表时间：
2021-11-15
影响因子：
15.9
通讯作者：
Wang, Yang
中科院分区：
文献类型：
--
作者：
Zhang, Wenjing;Sun, Yu;Wang, Yang
铁凋亡是一种铁依赖性非凋亡性细胞死亡，是一种高度调节的肿瘤抑制过程。然而，在肺癌进展过程中，RNA结合蛋白在调节铁凋亡逃避中的功能和机制仍不清楚。本文报道了RNA结合蛋白RBMS 1通过介导铁凋亡逃避参与肺癌的发生发展。通过shRNA介导的系统筛选，我们发现RBMS 1是一个关键的铁凋亡调节因子。临床上，RBMS 1在肺癌中升高，其高表达与患者生存率降低相关。相反，RBMS 1的缺失在体内和体外都抑制了肺癌的进展。RBMS 1与翻译起始因子eIF 3d直接相互作用，桥接SLC 7A 11的3 '-和5'-UTR。RBMS 1消融抑制了SLC 7A 11的翻译，减少了SLC 7A 11介导的胱氨酸摄取，并促进了铁凋亡。在靶向RBMS 1的药物筛选中，我们进一步发现盐酸去甲替林降低了RBMS 1的水平，从而促进了铁凋亡。重要的是，RBMS 1消耗或抑制盐酸去甲替林敏感的放射抵抗性肺癌细胞的放射治疗。我们的研究结果确立了RBMS 1作为铁凋亡的翻译调节因子和具有治疗潜力和临床价值的预后因子。
Ferroptosis, an iron-dependent non-apoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here we reported that the RNA binding protein RBMS1 participated in lung cancer development through mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 was a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3'- and 5'-UTRs of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake and promotes ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potentials and clinical values.