JMJD5 promotes chemotherapy sensitivity of cisplatin in NSCLC by enhancing DNA damage

Platinum-based chemotherapy remains a cornerstone in the treatment of advanced non-small cell lung cancer (NSCLC), yet its efficacy is frequently limited by drug resistance. JMJD5 (Jumonji Domain-Containing Protein 5) is a multifunctional protein implicated in tumor progression with enzymatic and non-enzymatic activities. While it has been reported to enhance the sensitivity of NSCLC cells to EGFR tyrosine kinase inhibitors (TKIs), its function in modulating response to conventional platinum chemotherapy is unknown.

The clinical relevance of JMJD5 was assessed via bioinformatics analysis of patient cohorts. In vitro functional assays in A549 and H1299 cells included overexpression modeling, cytotoxicity and colony formation, apoptosis analysis, and DNA damage assessment. An enzymatically inactive JMJD5 mutant was employed to dissect mechanism. The synergistic anti-tumor effect was validated in nude mouse xenograft models.

Low JMJD5 expression correlated with poorer overall survival in chemotherapy-treated NSCLC patients and was downregulated in tumor tissues post-chemotherapy. Cisplatin treatment reduced JMJD5 levels in vitro. Restoring JMJD5 expression significantly sensitized cells to cisplatin, enhancing its anti-proliferative and pro-apoptotic effects. This was associated with augmented DNA damage, evidenced by elevated γH2A.X. Crucially, the chemosensitizing function was independent of JMJD5's enzymatic activity. Mechanistically, JMJD5 overexpression suppressed cisplatin-induced Chk1/Chk2 phosphorylation, indicating impaired checkpoint activation. In vivo, JMJD5 overexpression combined with cisplatin markedly suppressed tumor growth, reducing both tumor volume and weight compared to cisplatin alone.

Our results demonstrate that JMJD5 enhances cisplatin sensitivity in NSCLC by amplifying DNA damage and apoptosis through a non-catalytic mechanism. JMJD5 thus represents a novel potential target for overcoming platinum resistance, offering a rationale for therapeutic strategies aimed at restoring or stabilizing its expression in combination with conventional chemotherapy.