RBM15 Mediated m6A Modification ofSRSF1 Inhibits Cuproptosis in Non-Small Cell Lung Cancer by Mediating ATP7B Alternative Splicing

Sep 30, 2026

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Inhibition of cuproptosis supports non-small cell lung cancer (NSCLC) progression. RNA-binding motif protein 15 (RBM15) is upregulated in NSCLC, yet its mechanism linking RBM15 to cuproptosis is not clear. This study examines RBM15’s regulatory role using elesclomol (ES-Cu) and tetrathiomolybdate (TTM) to induce or block cuproptosis, with transcript, protein, and RNA-binding analyses plus in vivo tumor xenografts. Results show RBM15 suppression reduces proliferation and invasion while promoting cuproptosis; copper chelation reverses these effects. Mechanistically, RBM15 enhances m6A modification of SRSF1 by recruiting YTHDF3, increasing ATP7B exon 21 splicing to inhibit cuproptosis and drive tumor growth. Overall, the RBM15/m6A/SRSF1/ATP7B axis stabilizes SRSF1 and sustains NSCLC aggressiveness.

LanguageEnglish

CategoryHealthcare

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Pages14

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Introduction

Cuproptosis and copper-mediated cell death

m6A modification and RBM15 in NSCLC

The Kaohsiung Journal of Medical Sciences ORIGINAL ARTICLE OPEN ACCESS RBM15 Mediated m6A Modification ofSRSF1 Inhibits Cuproptosis in Non-Small Cell Lung Cancer by Mediating ATP7B Alternative Splicing Shan-shan Mao1 | Dong-yu Wu1 | Rong-hua Cui2 | Xiao-zhen Cheng2 1Ward 1 of the Radiotherapy Department, The First Clinical College, The First Affiliated Hospital, Hainan Medical University, Haikou, Hainan, People's Republic of China | 2Department of Medical Oncology, Haikou People's Hospital, Haikou, Hainan, People's Republic of China Correspondence: Xiao-zhen Cheng ([zhenzhen0518hu@163.com](zhenzhen0518hu@163.com)) Received: 27 February 2025 | Revised: 23 July 2025 | Accepted: 7 August 2025 Funding: This work was supported by the National Natural Science Foundation of China (No. 82460476), Hainan Province Science and Technology Special Fund (No. ZDYF2024SHFZ039) and Academic Enhancement Support Program of Hainan Medical University (No. XSTS2025073) . Keywords: alternative splicing | cuproptosis | NSCLC | RBM15 | SRSF1 ABSTRACT 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 ofSRSF1 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. | Abbreviations: ATP7B, ATPase copper-transporting beta; BIN1, bridging integrator 1; CCK-8, Cell Counting Kit-8; DLD, dihydrolipoamide dehydrogenase; ES-Cu, elesclomol; FBS, fetal bovine serum; IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 3; IHC, immunohistochemical; m6A, N6-methyladenosine;
Me-RIP, methylated RNA immunoprecipitation; METTL3, methyltransferase 3; MYBL2B, B-Myb; NSCLC, non-small cell lung cancer; PBS, phosphate-buffered saline; RBM15, RNA-binding motif protein 15; RIP, RNA immunoprecipitation; RT-qPCR, quantitative real-time PCR; SLC31A1, solute carrier family 31 member 1; SR, serine/arginine; SRSF1, serine/arginine splicing factor 1; TMBIM6, transmembrane BAX inhibitor motif containing 6; WT, wild-type; YTHDF3, YT521-B homology domain family. | | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2025 The Author(s)

FAQs

Does the RBM15 axis affect tumor growth in vivo?

Yes. The study verifies that RBM15 promotes tumor growth in vivo by mediating SRSF1.

Sep 30, 2026

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