RCCD1-JMJD5 coordinate histone demethylation to promote platinum resistance in non-small cell lung cancer via FN1-mediated epithelial-mesenchymal transition.

Chemoresistance remains a major obstacle to effective treatment of non-small cell lung cancer (NSCLC), yet the epigenetic mechanisms underlying platinum resistance remain incompletely understood. Here, we show that Jumonji C domain-containing protein 5 (JMJD5) promotes platinum resistance in NSCLC cells and xenograft tumors while inducing a slow-proliferative, mesenchymal-like phenotype characterized by enhanced migration, invasion, spheroid formation, and epithelial-mesenchymal transition (EMT). Mechanistically, JMJD5 interacted with RCC1 domain-containing protein 1 (RCCD1), and cisplatin treatment promoted their nuclear accumulation concomitant with reduced H3K36me2 levels. RCCD1 depletion attenuated JMJD5-associated H3K36me2 demethylation and reversed EMT-associated phenotypes and cisplatin resistance, supporting RCCD1 as a functional cofactor of JMJD5-mediated chromatin remodeling. Fibronectin 1 (FN1) was further identified as a downstream effector of this pathway. Genetic or pharmacological inhibition of FN1 suppressed JMJD5-induced migration and invasion and restored cisplatin sensitivity. Notably, JMJD5-dependent FN1 protein accumulation required ongoing protein synthesis without a corresponding increase in FN1 mRNA, suggesting post-transcriptional regulation. Consistently, elevated FN1 expression was associated with unfavorable overall survival in patients with lung cancer. Collectively, these findings reveal a JMJD5-RCCD1-H3K36me2-FN1 regulatory axis linking chemotherapy-induced epigenetic remodeling to EMT-associated platinum resistance and suggest that disruption of this pathway may represent a potential strategy for overcoming chemoresistance in NSCLC.