Targeting RBM39 Suppresses Tumor Growth and Sensitizes Osteosarcoma Cells to Cisplatin

Osteosarcoma is one of the most common malignant primary bone tumors and lacks effective therapeutic targets. Recent studies have reported that RNA binding proteins (RBPs) could serve as promising therapeutic targets for cancers, as their critical roles in transcriptional regulation and RNA splicing. Nevertheless, the potential of pharmacologically inhibiting RBPs as a therapeutic strategy for patients with osteosarcoma remains unclear. In this study, we identified the RNA-binding protein RBM39 as a promising therapeutic target for osteosarcoma. RBM39 is essential for cell viability, and a higher expression of RBM39 was associated with poor prognosis in osteosarcoma. Mechanistically, RBM39 served as a coactivator of c-Jun to transcriptionally upregulate DKK1, leading to the activation of the GSK3β-NF-κB pathway. Importantly, our results reveal that the pharmacological depletion of RBM39 by using the anti-cancer aryl sulfonamide (E7820), a drug known for its oral bioavailability and safe administration, effectively represses osteosarcoma growth and sensitizes osteosarcoma cells to cisplatin treatment both in vitro and in vivo. Our findings unveil the crucial role of RBM39 in modulating tumor growth and cisplatin sensitivity in osteosarcoma cells, suggesting that the combination of aryl sulfonamides with cisplatin may benefit patients with osteosarcoma.