RNA-binding motif protein 15 promotes gastric cancer growth and drug resistance via USP10-mediated deubiquitination and stabilization of nuclear NRF2.

Gastric cancer (GC) continues to pose a major global health burden for which chemotherapy remains a first-line treatment. However, the efficacy of chemotherapy is often compromised by the development of chemoresistance, the underlying mechanisms of which remain elusive. Here, by profiling nascent RNA-binding proteins (nRBPs) and chromatin-binding proteins (chrBPs) in GC organoids, we identified RNA-binding motif protein 15 (RBM15) as a chromatin-associated nRBP (chr-nRBP) that is upregulated in GC cells and promotes tumour growth and chemoresistance. Mechanistically, RBM15 contains a microtubule-associated protein 1 A/1B-light chain 3 (LC3)-interacting region (LIR) motif, which is directed to the lysosome through autophagy, and impaired nucleophagy leads to its accumulation in tumours. Accumulated RBM15 recruits ubiquitin-specific peptidase 10 (USP10) to the nucleus, where it deubiquitinates and stabilizes nuclear factor erythroid 2-related factor 2 (NRF2), thereby decreasing its proteasome-mediated degradation. This RBM15-USP10-NRF2 axis drives resistance to cisplatin and 5-fluorouracil (5-FU) both in vitro and in vivo. Disruption of this pathway sensitizes GC cells to chemotherapy and suppresses tumour growth. Collectively, our findings suggest that RBM15 is both a predictive biomarker and a therapeutic target for overcoming chemotherapy resistance in GC cells.