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RBM15 Mediated m6A Modification of SRSF1 Inhibits Cuproptosis in Non-Small Cell Lung Cancer by Mediating ATP7B
Shan-Shan Mao1, Dong-Yu Wu1, Rong-Hua Cui2
1Ward 1 of the Radiotherapy Department, The First Clinical College, The First Affiliated Hospital, Hainan Medical University, Haikou, Hainan, People's Republic of China.
The Kaohsiung Journal of Medical Sciences
|September 9, 2025
Summary
RNA-binding motif protein 15 (RBM15) promotes non-small cell lung cancer (NSCLC) by inhibiting cuproptosis. RBM15 enhances SRSF1 stability via m6A modification, leading to altered ATP7B splicing and tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Cuproptosis inhibition is implicated in non-small cell lung cancer (NSCLC) development.
- RNA-binding motif protein 15 (RBM15) expression is elevated in NSCLC, but its role in cuproptosis is unknown.
Purpose of the Study:
- To investigate the function of RBM15 in regulating cuproptosis within NSCLC.
- To elucidate the molecular mechanisms linking RBM15, cuproptosis, and NSCLC progression.
Main Methods:
- Cellular assays (EdU, CCK-8, Transwell, flow cytometry) in A549 cells treated with elesclomol (ES-Cu) or tetrathiomolybdate (TTM).
- Gene and protein expression analysis (RT-qPCR, western blotting).
- RNA immunoprecipitation (RIP) and m6A immunoprecipitation (MeRIP) assays to study RBM15, YTHDF3, and SRSF1 interactions.
- In vivo tumor xenograft models in nude mice and copper level assessment.
Main Results:
- RBM15 suppression in NSCLC cells increased cuproptosis, reduced proliferation and invasion, effects reversed by copper chelators (TTM).
- RBM15 promotes SRSF1 m6A modification by recruiting YTHDF3, enhancing SRSF1 stability.
- SRSF1 promotes NSCLC proliferation and invasion and inhibits cuproptosis by regulating ATP7B alternative splicing, specifically exon 21.
Conclusions:
- RBM15 promotes NSCLC progression by mediating the m6A modification of SRSF1, which in turn regulates ATP7B alternative splicing to inhibit cuproptosis.
- The RBM15/m6A/SRSF1/ATP7B axis represents a novel therapeutic target for NSCLC.
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