Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression

Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity. [Display omitted] •CBP acetylates human p53 at K101 and mouse p53 at K98•K98 acetylation of mouse p53 contributes to regulation of certain metabolic genes•p534KR98 is defective in suppressing tumor growth•Ferroptosis and repression of SLC7A11 are defective in p534KR98-expressing cells Wang et al. show that K98 acetylation of mouse p53 by CBP further contributes to the regulation of p53 transcriptional function by other known p53 acetylations (K117/161/162). Simultaneous absence of acetylation at K98 and at other positions in the DNA-binding domain results in the loss of tumor suppression in xenografts and ferroptosis.