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

Therapeutic activation of ferroptosis is a potential strategy to induce cell death in cancer. Deciphering the epigenetic regulation of ferroptosis could provide insights into effective approaches for enhancing ferroptosis in cancer cells. In this study, we identified CRB2 as an epigenetic modulator of ferroptosis in head and neck squamous cell carcinoma (HNSCC). CRB2 expression correlated with the expression of ferroptosis-related genes and improved prognosis in patients with HNSCC. Ferroptosis inducers erastin and RSL3 significantly increased CRB2 expression, and overexpression of CRB2 sensitized HNSCC to ferroptosis, suppressing growth in vitro and in vivo. CRB2 upregulation led to an increase in the dimethylation of histone H4 lysine 20 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 the degradation of LSD1(E8A) and subsequently increasing histone H4 lysine 20 dimethylation levels. Taken together, these results indicate that CRB2 stimulates ferroptosis by activating an epigenetic axis, suggesting that the upregulation of CRB2 is a potential therapeutic strategy for HNSCC. SIGNIFICANCE: CRB2 epigenetically inhibits SCL7A11-GPX4 signaling to promote ferroptosis and suppress tumor growth in head and neck squamous cell carcinoma, providing insights that could guide ferroptosis-activating treatment approaches.