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METTL1/WDR4-mediated m7G Hypermethylation of SCLT1 mRNA Promotes Gefitinib Resistance in NSCLC
Shaoxuan Zhou1,2, Yueqin Wang1,2, Jingyao Wei1,2
1Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Abstract:
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have produced durable complete responses, but the eventual development of acquired resistance presents a major challenge in the treatment of non-small cell lung cancer (NSCLC). N7-methylguanosine (m7G), a prevalent post-transcriptional modification within RNA, plays regulatory roles in RNA stability, expression dynamics, and functional diversity. Despite these insights, the contribution of m7G methylation to EGFR-TKIs resistance remains poorly characterized. Here, we demonstrate that internal m7G modifications of mRNA and their associated methyltransferase complex, methyltransferase-like 1 (METTL1)/WD repeat domain 4 (WDR4), are significantly elevated in NSCLC specimens, which correlates with therapeutic resistance. Functional assays confirmed that METTL1/WDR4 enhances gefitinib resistance in both cellular and animal models through internal RNA m7G methyltransferase activity in NSCLC. Mechanistically, m7G MeRIP-seq combined with RNA-seq identified sodium channel and clathrin linker 1 (SCLT1) as the m7G target of METTL1/WDR4. METTL1/WDR4 knockdown led to decreased methylation level and mRNA stability of the SCLT1 transcript. Importantly, overexpression of wild-type METTL1, but not its catalytically inactive mutant, restored mRNA stability. Furthermore, METTL1/WDR4-mediated m7G modification of SCLT1 regulates gefitinib resistance by activating the NF-κB signaling. Our findings reveal the crucial role of aberrant mRNA internal m7G modification in EGFR-TKIs resistance, suggesting that targeting the METTL1/WDR4-SCLT1-NF-κB axis holds a promising therapeutic potential for overcoming EGFR-TKIs resistance.
Insights
Aberrant N7-methylguanosine (m7G) RNA modification, driven by METTL1/WDR4, promotes resistance to EGFR-TKIs in non-small cell lung cancer (NSCLC). Targeting the METTL1/WDR4-SCLT1-NF-κB pathway may overcome this resistance.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective against non-small cell lung cancer (NSCLC), but acquired resistance limits long-term efficacy.
- N7-methylguanosine (m7G) is a key RNA modification influencing RNA fate, yet its role in EGFR-TKI resistance is largely unknown.
Purpose of the Study:
- To investigate the role of m7G RNA modification and its associated methyltransferase complex (METTL1/WDR4) in acquired resistance to EGFR-TKIs in NSCLC.
- To identify the downstream targets and signaling pathways regulated by METTL1/WDR4-mediated m7G modification in the context of gefitinib resistance.
Main Methods:
- Analysis of m7G modification levels and METTL1/WDR4 expression in NSCLC specimens.
- Functional studies using cellular and animal models to assess the impact of METTL1/WDR4 on gefitinib resistance.
- m6A-specific RNA immunoprecipitation followed by sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) to identify m7G targets.
- Western blotting and reporter assays to investigate signaling pathway activation.
Main Results:
- Elevated m7G modification and METTL1/WDR4 expression in NSCLC tissues correlated with therapeutic resistance.
- METTL1/WDR4 overexpression enhanced gefitinib resistance in NSCLC cells and xenograft models.
- SCLT1 was identified as a direct target of METTL1/WDR4, with its mRNA stability and expression regulated by m7G modification.
- METTL1/WDR4-mediated SCLT1 m7G modification activated the NF-κB signaling pathway, contributing to gefitinib resistance.
Conclusions:
- Aberrant internal mRNA m7G modification by the METTL1/WDR4 complex plays a critical role in acquired resistance to EGFR-TKIs in NSCLC.
- The METTL1/WDR4-SCLT1-NF-κB axis represents a novel mechanism driving gefitinib resistance.
- Targeting the METTL1/WDR4-SCLT1-NF-κB pathway offers a potential therapeutic strategy to overcome EGFR-TKI resistance in NSCLC.
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