JMJD6 promotes radioresistance of non-small cell lung cancer via epigenetic regulation of EHF

Abstract Though radiation therapy (RT) is widely used in lung cancer at all stages for local tumor control, the long-term efficacy of radiotherapy is largely restricted by radioresistance as frequently observed in the clinical setting, eventually leading to cancer recurrence. With the advent of targeted therapies, we observed a dramatic uptick in the clinical outcomes of non–small cell lung cancer (NSCLC) patients. JMJD6 was initially identified as an arginine 2 histone H3 (H3R2) and arginine 3 histone H4 (H4R3) arginine demethylase, and was later confirmed to be closely related to the occurrence and development of various cancers. In the present study, we found that RT induced the upregulation of JMJD6 which promoted the transcription of Ets homologous factor (EHF) and downstream pluripotency factor genes via the demethylation of H4R3me2s. Analyses results from matched human NSCLC tissues demonstrated that JMJD6 was upregulated in radioresistant NSCLC cells and in tumors of NSCLC patients, which indicated worse prognosis and higher metastasis risk in patients. These findings are of therapeutic importance for the design of novel therapies to prevent post-RT metastasis and to improve the long-term efficacy of radiotherapy in lung cancer.