RBMS1 regulates lung cancer ferroptosis through translational control of SLC7A11
| Autor: | Zhaochao Xu, Chao Peng, Han Liu, Luning Wang, Qingzhi Zhao, Wenxia He, Jinyao Zhao, Wenjing Zhang, Xiaoling Li, Lu Bai, Yun Yang, Hai-long Piao, Sirui Zhang, Yue Yin, Qinglong Qiao, Wenting Gao, Lili Zhi, Shujun Fan, Dan Chen, Yang Wang, Chaoqun Chen, Huan Chen, Yu Sun, Yangfan Qi, Jinrui Zhang, Quentin Liu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Programmed cell death
Lung Neoplasms Amino Acid Transport System y+ Regulator RNA-binding protein SLC7A11 Radiation Tolerance Mice Radioresistance Cell Line Tumor medicine Animals Ferroptosis Humans Lung cancer biology Proto-Oncogene Proteins c-ets business.industry RNA-Binding Proteins Translation (biology) General Medicine medicine.disease DNA-Binding Proteins HEK293 Cells Nortriptyline Hydrochloride Protein Biosynthesis biology.protein Cancer research business Transcription Factors Research Article |
| Zdroj: | J Clin Invest |
| ISSN: | 1558-8238 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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