p53 Promotes Ferroptosis during ROS Stress to Suppress Tumorigenesis

Many human cancers exhibit inactivation of p53, which is important for stress-induced cell-cycle arrest, apoptosis, and senescence. These functions of p53 are thought to underlie its tumor-suppressive activity and are regulated by acetylation of p53. However, an acetylation-defective mutant p53 (p53^3KR) retains tumor-suppressive functions, suggesting a role for the modulation of metabolic p53 targets in tumor suppression. Jiang, Kon, and colleagues found that p53 bound the promoter region of solute carrier family 7 member 11 (SLC7A11), which encodes a component of the cystine/glutamate antiporter, resulting in reduced expression of SLC7A11 and decreased cystine uptake. Acetylation-defective mutant p53^3KR retained the ability to transcriptionally inhibit SLC7A11 expression and suppress cystine uptake, similar to wild-type p53, indicating that this function is independent of the role of p53 in cell-cycle arrest, apoptosis, and senescence. p53-mediated repression of SLC7A11 resulted in the induction of ferroptosis, an iron-dependent, nonapoptotic form of cell death, in both p53–wild-type and p53^3KR cells in response to reactive oxygen species (ROS)–induced stress, but not DNA damage. Importantly, SLC7A11 was upregulated in multiple types of human cancers, and overexpression of SLC7A11 rescued human cancer cells from p53^3KR-induced ferroptosis and significantly diminished the tumor-suppressive function of p53^3KR in xenograft models, indicating that repression of SLC7A11 is necessary for the tumor-suppressive function of p53. Furthermore, p53-mediated suppression of Slc7a11 and induction of ferroptosis contributed to the developmental abnormalities observed in Mdm2-null embryos, supporting a role for p53-driven metabolic regulation in embryonic development. Together, these data identify a critical role of this noncanonical metabolic function of p53 in tumor suppression via the regulation of SLC7A11-dependent ferroptotic cell death.

Jiang L, Kon N, Li T, Wang SJ, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumor suppression. Nature 2015;520:57–62.

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