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

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.