RNA Structural Dynamics Modulate EGFR-TKI Resistance Through Controlling YRDC Translation in NSCLC Cells.
10.1016/j.gpb.2022.10.006
- Author:
Boyang SHI
1
;
Ke AN
1
;
Yueqin WANG
2
;
Yuhan FEI
3
;
Caixia GUO
4
;
Qiangfeng CLIFF ZHANG
3
;
Yun-Gui YANG
5
;
Xin TIAN
6
;
Quancheng KAN
7
Author Information
1. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China; Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.
2. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China.
3. MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
4. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China.
5. Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China. Electronic address: ygyang@big.ac.cn.
6. Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China. Electronic address: tianx@zzu.edu.cn.
7. Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China. Electronic address: kanqc@zzu.edu.cn.
- Publication Type:Journal Article
- Keywords:
EGFR-TKI resistance;
ELAVL1;
Non-small cell lung cancer;
RNA structure;
YRDC
- MeSH:
Humans;
Carcinoma, Non-Small-Cell Lung/genetics*;
Cell Line, Tumor;
Drug Resistance, Neoplasm/genetics*;
ErbB Receptors/metabolism*;
GTP-Binding Proteins/therapeutic use*;
Lung Neoplasms/genetics*;
Mutation;
Protein Kinase Inhibitors/therapeutic use*;
RNA;
RNA-Binding Proteins/genetics*;
Tyrosine Kinase Inhibitors/therapeutic use*
- From:
Genomics, Proteomics & Bioinformatics
2023;21(4):850-865
- CountryChina
- Language:English
-
Abstract:
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). Rapidly acquired resistance to EGFR-TKIs is a major hurdle in successful treatment. However, the mechanisms that control the resistance of EGFR-TKIs remain largely unknown. RNA structures have widespread and crucial functions in many biological regulations; however, the functions of RNA structures in regulating cancer drug resistance remain unclear. Here, the psoralen analysis of RNA interactions and structures (PARIS) method is used to establish the higher-order RNA structure maps of EGFR-TKIs-resistant and -sensitive cells of NSCLC. Our results show that RNA structural regions are enriched in untranslated regions (UTRs) and correlate with translation efficiency (TE). Moreover, yrdC N6-threonylcarbamoyltransferase domain containing (YRDC) promotes resistance to EGFR-TKIs. RNA structure formation in YRDC 3' UTR suppresses embryonic lethal abnormal vision-like 1 (ELAVL1) binding, leading to EGFR-TKI sensitivity by impairing YRDC translation. A potential therapeutic strategy for cancer treatment is provided using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism through which the RNA structure switch modulates EGFR-TKI resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner.
