Regulation of ferroptosis by transcription factor E2F1.

The E2F family of transcription factors plays multiple roles in cell cycle regulation. E2F can be inhibited by binding to RB proteins, an interaction that is regulated by CDK phosphorylation of RB. We previously observed that CDKs, RB, and E2F regulate ferroptosis, a type of programmed cell death characterized by catastrophic peroxidation of membrane lipids. Here we investigate the impact of E2F on ferroptosis. E2F1 regulates both pro and anti-ferroptotic proteins including ALOX5, MYC, SLC7A11, ATF4, and GPX4 and finally renders a net inhibitory role in ferroptosis. Interestingly, we also obtained evidence for a cell type dependent compensatory effect of E2F3 upon E2F1 depletion. Specifically, downregulation of ferroptotic genes upon E2F1 knockdown fails to occur in an osteosarcoma cell line which upregulates E2F3 under these conditions. Taken together, our study identifies a number of E2F targets with the potential to affect ferroptotic sensitivity.