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Published on: January 7, 2019
Long non-coding RNA CASC9 promotes gefitinib resistance in NSCLC by epigenetic repression of DUSP1
Zhenyao Chen1, Qinnan Chen1, Zhixiang Cheng1
1Cancer Medical Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.
Abstract:
Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, has greatly affected clinical outcomes in non-small cell lung cancer (NSCLC) patients. The long noncoding RNAs (lncRNAs) are known to regulate tumorigenesis and cancer progression, but their contributions to NSCLC gefitinib resistance remain poorly understood. In this study, by analyzing the differentially expressed lncRNAs in gefitinib-resistant cells and gefitinib-sensitive cells in the National Institute of Health GEO dataset, we found that lncRNA CASC9 expression was upregulated, and this was also verified in resistant tissues. Gain and loss of function studies showed that CASC9 inhibition restored gefitinib sensitivity both in vitro and in vivo, whereas CASC9 overexpression promoted gefitinib resistance. Mechanistically, CASC9 repressed the tumor suppressor DUSP1 by recruiting histone methyltransferase EZH2, thereby increasing the resistance to gefitinib. Furthermore, ectopic expression of DUSP1 increased gefitinib sensitivity by inactivating the ERK pathway. Our results highlight the essential role of CASC9 in gefitinib resistance, suggesting that the CASC9/EZH2/DUSP1 axis might be a novel target for overcoming EGFR-TKI resistance in NSCLC.
Insights
Long noncoding RNA CASC9 promotes gefitinib resistance in non-small cell lung cancer (NSCLC) by inhibiting DUSP1. Targeting the CASC9/EZH2/DUSP1 pathway may overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib are crucial for non-small cell lung cancer (NSCLC) treatment.
- Resistance to EGFR-TKIs significantly compromises patient outcomes in NSCLC.
- The role of long noncoding RNAs (lncRNAs) in mediating gefitinib resistance in NSCLC is not fully elucidated.
Purpose of the Study:
- To investigate the role of lncRNAs in the development of gefitinib resistance in NSCLC.
- To identify specific lncRNAs involved in EGFR-TKI resistance.
- To elucidate the molecular mechanisms by which identified lncRNAs contribute to gefitinib resistance.
Main Methods:
- Differential expression analysis of lncRNAs in gefitinib-resistant versus sensitive NSCLC cells using the NIH GEO dataset.
- In vitro and in vivo gain- and loss-of-function studies to assess the impact of CASC9 on gefitinib sensitivity.
- Mechanistic investigations involving EZH2 recruitment, DUSP1 repression, and ERK pathway activation.
Main Results:
- lncRNA CASC9 was found to be significantly upregulated in gefitinib-resistant NSCLC cells and tissues.
- Inhibition of CASC9 restored gefitinib sensitivity in vitro and in vivo.
- CASC9 overexpression conferred gefitinib resistance by recruiting EZH2 to repress the tumor suppressor DUSP1, leading to ERK pathway activation.
Conclusions:
- lncRNA CASC9 plays a critical role in promoting gefitinib resistance in NSCLC.
- The CASC9/EZH2/DUSP1 axis represents a potential therapeutic target for overcoming EGFR-TKI resistance in NSCLC patients.
- Restoring DUSP1 expression or inhibiting the CASC9/EZH2 interaction could be strategies to re-sensitize NSCLC to gefitinib.
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