CRB2 Activates an Epigenetic Axis to Promote Ferroptosis in Head and Neck Squamous Cell Carcinoma

Abstract Therapeutic activation of ferroptosis is a potential strategy to induce cell death in cancer. Deciphering epigenetic regulation of ferroptosis could provide insights into effective approaches for enhancing ferroptosis in cancer cells. Here, we identified CRB2 as an epigenetic modulator of ferroptosis in head and neck squamous cell carcinoma (HNSCC). CRB2 expression correlated with expression of ferroptosis-related genes and improved prognosis in HNSCC patients. Ferroptosis inducers Erastin and RSL3 significantly increased CRB2 expression, and overexpression of CRB2 sensitized HNSCC to ferroptosis to suppress growth in vitro and in vivo. CRB2 upregulation led to an increase in dimethylation of histone H4 lysine 20 (H4K20me2) in the promoter region of the ferroptosis inhibitor SLC7A11, which epigenetically inhibited its transcription and induced ferroptosis in HNSCC. Mechanistically, CRB2 hindered the interaction between the E8A isoform of the histone lysine demethylase LSD1 and the deubiquitinase USP7, thereby facilitating degradation of LSD1(E8A) and subsequently increasing H4K20me2 levels. Taken together, these results indicate that CRB2 stimulates ferroptosis by activating an epigenetic axis, suggesting upregulation of CRB2 as a potential therapeutic strategy for HNSCC.