G9a deficiency activates TMEM27 to promote ferroptosis and enhances radiosensitivity in head and neck squamous cell carcinoma.

Epigenetic regulation, which modulates gene expression without altering the DNA sequence, plays a critical role in adaptive responses to environmental stressors, including irradiation. In this study, we investigated the role of histone H3K9 methylation in radiotherapy for head and neck squamous cell carcinoma (HNSCC). We identified G9a, a key lysine methyltransferase, as a critical regulator of H3K9me2 methylation in HNSCC radiotherapy. Inhibition of G9a using the small molecule inhibitor BRD4770 significantly enhanced radiosensitivity in HNSCC cells. Ferroptosis, a recently discovered form of iron-dependent cell death driven by lipid peroxidation, was found to play a pivotal role in radiotherapy-induced cell death and tumor suppression. RNA sequencing and KEGG pathway analysis revealed that G9a knockout increased radiosensitivity primarily by inducing ferroptosis. Further screening identified TMEM27 as a downstream target gene, and ChIP-qPCR confirmed that G9a binds to the H3K9me2 site of TMEM27, regulating its transcription. Importantly, we demonstrated that G9a-mediated expression of TMEM27 depends on its histone methyltransferase activity. In summary, this study reveals that G9a deficiency enhances radiosensitivity in HNSCC by activating TMEM27 to promote ferroptosis, providing a novel therapeutic strategy for overcoming radiotherapy resistance.