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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 22 (11 15 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 34609966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Transport System y+
• DNA-Binding Proteins
• ELF3 protein, human
• Proto-Oncogene Proteins c-ets
• RBMS1 protein, human
• RNA-Binding Proteins
• SLC7A11 protein, human
• Transcription Factors

Topics

• Amino Acid Transport System y+ (genetics)
• Animals
• Cell Line, Tumor
• DNA-Binding Proteins (physiology)
• Ferroptosis
• HEK293 Cells
• Humans
• Lung Neoplasms (pathology, radiotherapy)
• Mice
• Protein Biosynthesis
• Proto-Oncogene Proteins c-ets (physiology)
• RNA-Binding Proteins (physiology)
• Radiation Tolerance
• Transcription Factors (physiology)