NAA50-mediated SLU7 stabilization promotes cisplatin resistance in bladder cancer via regulating MAP3K3 mRNA nuclear export and p38 MAPK activation.

BACKGROUND: Cisplatin-based chemotherapy is first-line for muscle-invasive bladder cancer (BLCA), but chemoresistance remains the primary barrier to clinical efficacy. RNA-binding proteins (RBPs) orchestrate post-transcriptional gene regulation and are increasingly implicated in cancer chemoresistance; however, the role and regulatory mechanism of the splicing factor RBP SLU7 in BLCA cisplatin resistance remain completely unknown.

METHODS: We analyzed SLU7 expression and clinical prognosis in two independent cisplatin-treated BLCA cohorts (GSE87304, GSE169455). Cisplatin-resistant BLCA cell lines (T24-CIS, UMUC3-CIS) were established for functional assays (CCK-8, qRT-PCR, western blotting). Molecular interactions were validated by RIP-qPCR, immunofluorescence(IF), RNA-FISH, nucleocytoplasmic fractionation, co-immunoprecipitation (co-IP), and mass spectrometry (MS). In vivo therapeutic efficacy was assessed in BLCA xenograft models.

RESULTS: SLU7 was significantly upregulated in cisplatin-resistant BLCA cells, and high SLU7 expression independently predicted poor cancer-specific survival (CSS) and recurrence-free survival (RFS) in cisplatin-treated patients. SLU7 knockdown suppressed MAP3K3 expression, inhibited p38 MAPK pathway, and restored cisplatin sensitivity. Mechanistically, SLU7 directly bound MAP3K3 mRNA and promoted its nuclear export-a non-canonical function independent of its canonical splicing activity. MS and Co-IP identified NAA50 as the upstream regulator that catalyzes N-terminal acetylation of SLU7 to prevent its ubiquitin-proteasomal degradation, thereby sustaining SLU7 stability. Pharmacological inhibition of NAA50 with Naa50-IN-1 destabilized SLU7, blocked the MAP3K3-p38 axis, and reversed cisplatin resistance in vitro and in vivo.

CONCLUSIONS: We uncover a novel NAA50-SLU7-MAP3K3-p38 MAPK regulatory axis that drives cisplatin resistance in BLCA. NAA50-mediated N-terminal acetylation stabilizes SLU7, which in turn facilitates MAP3K3 mRNA nuclear export to activate p38 MAPK signaling. Targeting NAA50 represents a promising therapeutic strategy to overcome cisplatin resistance in BLCA, and SLU7 serves as a predictive biomarker for cisplatin response.