<scp>RBM15</scp> Mediated <scp>m6A</scp> Modification of <scp>SRSF1</scp> Inhibits Cuproptosis in Non‐Small Cell Lung Cancer by Mediating <scp>ATP7B</scp> Alternative Splicing

Inhibition of cuproptosis contributes to the development of non-small cell lung cancer (NSCLC). The expression of RNA-binding motif protein 15 (RBM15) is upregulated in NSCLC. Nonetheless, its relationship with cuproptosis remains unclear. This study aimed to explore the role of RBM15 in regulating cuproptosis in NSCLC. A549 cells were treated with elesclomol (ES-Cu) and tetrathiomolybdate (TTM) to induce or inhibit cellular cuproptosis. EdU, CCK-8, Transwell assays, and flow cytometry were used to detect cellular phenotypes. The expression levels of relevant genes and proteins were analyzed using RT-qPCR and western blotting. RIP and MeRIP were utilized to investigate the interaction of RBM15 and YT521-B homology domain family-3 (YTHDF3) with serine/arginine splicing factor 1 (SRSF1). The effect of the RBM15/m6A/SRSF1/ATP7B axis on tumor growth was evaluated using tumor xenografts in nude mice. Copper levels were assessed using commercially available kits. In NSCLC cells, RBM15 suppression inhibited proliferation and invasion while promoting cuproptosis; however, treatment with TTM (copper chelators) reversed the effect of sh-RBM15. ES-Cu treatment inhibited cell proliferation and invasion, and RBM15 knockdown further promoted the effect of ES-Cu, but upregulated RBM15 reversed the regulatory effect of ES-Cu. Mechanistically, RBM15 promoted the m6A modification of SRSF1 by recruiting YTHDF3. Increased SRSF1 enhanced ATPase copper-transporting beta (ATP7B) exon 21 splicing. Furthermore, SRSF1 promoted cell proliferation and invasion and inhibited cuproptosis by regulating ATP7B alternative splicing. Finally, we verified that RBM15 promoted tumor growth by mediating SRSF1 in vivo. In short, RBM15-mediated m6A modification enhanced SRSF1 stability, and SRSF1 promoted ATP7B alternative splicing to inhibit cuproptosis, thereby promoting NSCLC cell proliferation and tumor growth.