RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11
Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang
Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang
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Research Article Cell biology Oncology

RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11

Abstract

Ferroptosis, an iron-dependent nonapoptotic 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 report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is 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′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted 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 potential and clinical value.

Authors

Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang

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Figure 10

RBMS1 interacts with eIF3d to bridge the 3′- and 5′-UTR of SLC7A11 to promote its translation.

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RBMS1 interacts with eIF3d to bridge the 3′- and 5′-UTR of SLC7A11 to pr...
(A) SLC7A11-fluc-T2 and SLC7A11-fluc-T3 were transiently transfected into eIF3d-overexpressing H1299 cells. (B) SLC7A11-fluc-T3 was transiently transfected into RBMS1-depleted H1299 cells with or without eIF3d overexpression. For A and B, data represent mean ± SEM (n = 3). P values were calculated from unpaired t test (A) or 1-way ANOVA with Tukey’s multiple comparison test (B). (C) The level of SLC7A11 was examined in eIF3d-depleted H1299 cells. (D) The levels of SLC7A11, RBMS1, and eIF3d were examined in H1299 cells expressing RBMS1, with or without eIF3d depletion. (E) Binding of SLC7A11 5′- and 3′-UTR with RBMS1 was examined by RNA-IP (RIP) in A549 cells expressing FLAG-RBMS1. (F) Binding of SLC7A11 5′- and 3′-UTR with eIF3d was examined by RNA-IP in A549 cells expressing FLAG-eIF3d. (G) Binding of SLC7A11 3′- or 5′-UTR with eIF3d was examined by RNA-IP assay in A549 cells expressing FLAG-eIF3d with or without RBMS1 depletion. (H) Binding of SLC7A11 5′- or 3′-UTR with RBMS1 was examined by RNA-IP assay in A549 cells expressing FLAG-RBMS1 with or without eIF3d depletion. (I) Schematic of the model for how RBMS1 regulates the translation of SLC7A11.