TET1-mediated DNA hydroxymethylation controlling ferroptosis resistance in cancer [ChIP-seq]

Ferroptosis, a non-apoptotic programmed cell death marked by iron-dependent lipid peroxidation, is closely associated with cancer. Despite of intensive investigation about the molecular pathways underlying ferroptosis, the mechanism that determines the disparity of cancer cell vulnerability to ferroptosis remains unclear. Here we show that the expression level of TET1, the founding member of the ten-eleven translocation (TET) family of enzymes that mediate DNA 5-hydroxymethylation, determines the susceptibility of cancer cells to ferroptosis. In ferroptosis resistant cells, the expression level of TET1 was remarkably higher than that of the sensitive cells. Cell response to ferroptosis could be affected by interfering TET1 expression. TET1 promoted DNA 5hmC modification at its target gene GCLM, activated both the canonical glutathione (GSH) synthesis, and the non-cannonical γ-glutamyl-peptide accumulation, and thus, protected cancer cells against ferroptosis. Our results uncover the role of TET1 as a ferroptotic defensor in cancer, and suggest the translational potential of targeting the TET/GCLM axis in cancer therapy.