Integrative analysis of non-small cell lung cancer identifies Jumonji domain-containing 6/ETS homologous factor axis as a target to overcome radioresistance.

Radiation therapy (RT) is a key treatment strategy for lung cancer, yet its efficacy is frequently compromised by radioresistance. The combination of RT with targeted therapies enhances treatment outcomes for non-small cell lung cancer (NSCLC). This study aims to investigate new mechanisms of metastasis after RT for NSCLC and improve the durability of the benefits of radiotherapy for lung cancer patients. This integrative study utilized human NSCLC tissue arrays, bulk RNA-sequencing, CUT&Tag sequencing, and single-cell RNA-sequencing to identify gene alterations induced by RT. In vitro experiments and animal studies were used to investigate the role of Jumonji domain-containing 6 (JMJD6)/ETS homologous factor (EHF) axis in post-RT metastasis of NSCLC. RT triggered the upregulation of JMJD6 in NSCLC tissues. This upregulation led to the activation of EHF and the subsequent transcription of pluripotency factor genes through the demethylation of H4R3me2s. JMJD6/EHF axis plays a critical role in NSCLC cell metastasis, potentially through the TGF-β/SMAD and AKT/ERK signaling pathways. These findings suggest JMJD6 as a potential therapeutic target to combat post-RT metastasis in NSCLC.