Work

MiR-493–3p suppresses the DPY-30 histone methyltransferase complex regulatory subunit to attenuate gefitinib resistance in lung cancer

Year: 2025

Type: article

Abstract: • miRNA-493–3p was found to be significantly downregulated in gefitinib-resistant lung cancer cell lines (A549GFR and H1975GFR). This microRNA directly targets DPY30, a gene involved in cell cycle progression and stemness maintenance. • DPY30 was upregulated in gefitinib-resistant cells, contributing to resistance by promoting stemness and cell cycle progression. • Upregulation of miRNA-493–3p suppressed DPY30 expression, reversing gefitinib resistance and reducing tumor stemness both in vitro and in vivo. • The study highlights the miRNA-493–3p/DPY30 pathway as a potential therapeutic target to sensitize lung cancer cells to gefitinib, offering a promising strategy for combating drug resistance in lung cancer treatment. Resistance to treatment remains a significant challenge in the management of lung cancer. The mechanisms underlying resistance include gene mutation, tumor heterogeneity, and immune evasion. Dysregulation of functional genes and miRNAs is a consistent feature of tumors displaying drug resistance. In this study, we aimed to characterize and identify dysregulated miRNAs and their role in gefitinib-resistant lung cancer. The gefitinib-resistant lung cancer cell line A549GFR was generated and subjected to small RNA sequencing to identify dysregulated microRNAs. We identified miR-493–3p as one of the significantly downregulated miRNAs. DPY30 was identified as a potential target of miR-493–3p To further investigate this phenomenon, we employed qPCR, Western blot, flow cytometry, immunohistochemistry, flow cytometry and apoptosis assays for different biological parameters. The results revealed that DPY30, which is critical for regulating cell cycle progression and maintaining stemness, was upregulated in both the A549GFR and the EGFR-mutant H1975GFR cell lines. We confirmed that DPY30 is indeed a target of miR-493–3p Further analysis revealed that downregulation of DPY30 reversed the resistance characteristics of both cell lines, including reversion of stemness and inhibition of cell cycle progression. Upregulation of miR-493–3p suppressed DPY30 expression, leading to similar effects. These in vitro results were also observed in vivo when gefitinib-resistant tumor xenografts were established in nude mice. This research highlights the role of miR-493–3p in lung cancer gefitinib-responsive mechanisms by targeting the DPY30-mediated resistance pathway. Therefore, the miR-493–3p/DPY30 axis could be a promising target for sensitizing lung cancer to gefitinib.

Source: Translational Oncology

DOI: 10.1016/j.tranon.2025.102570