Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression

Abstract

Summary 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 identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). While 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.

p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells

“…Our results appear to contradict the findings that expression of acetylation-defective p53 mutants (i.e., 3KR) reduce system x c − function and sensitize cancer cells to ferroptosis (Jiang et al, 2015; Wang et al, 2016). However, acetylation-defective p53 mutants are unable to induce p21 (Jiang et al, 2015).…”

“…How wild-type p53 suppresses tumor formation remains unclear despite decades of study. Recently, acetylation-defective p53 mutants were shown to promote ferroptosis, an iron-dependent, oxidative and non-apoptotic form of cell death (Jiang et al, 2015; Wang et al, 2016). These p53 mutants are unable to induce apoptosis, cell-cycle arrest, or senescence, yet retain the ability to prevent tumor formation in mice (Li et al, 2012), suggesting that p53-induced ferroptosis could be responsible for tumor suppression.…”

NRF2 Is a Major Target of ARF in p53-Independent Tumor Suppression

“…Our previous study showed that p53 3KR , an acetylation-defective mutant that fails to mediate p53-dependent cell cycle arrest, apoptosis and senescence, still retains the ability to induce ferroptosis through downregulation of SLC7A11 expression (Jiang et al; 2015; Wang et al, 2016). To test the role of ARF in modulating ferroptotic responses upon ROS treatment, we established a tet-on p53-null H1299 cell line in which ARF expression can be induced by tetracycline.…”

“…Although cell-cycle arrest, senescence and apoptosis serve as critical barriers to cancer development, accumulating evidence suggests that loss of p53-dependent cell cycle arrest, apoptosis, and senescence is not sufficient to abrogate the tumor suppression activity of p53. We recently showed that the p53 tumor suppressor sensitizes cells to ferroptosis by repressing transcription of the SLC7A11 gene, which encodes a key component of the cystine/glutamate antiporter (Jiang et al, 2015; Wang et al, 2016; Jennis et al, 2016). Cystine uptake is critical for glutathione synthesis to buffer reactive oxygen species (ROS).…”

“…Although the precise mechanism by which SLC7A11 modulates ferroptosis needs to be further elucidated, suppression of SLC7A11 expression results in intracellular cysteine depletion, which makes the cells incapable of defending oxidative stress and susceptible to ferroptotic cell death. In addition, p53-mediated ferroptosis appears to act as a barrier to cancer development since it can suppress tumor formation independent of p53-mediated cell cycle arrest, senescence and apoptosis (Jiang et al, 2015; Wang et al, 2016). Of note, SLC7A11 is highly expressed in human tumors (Jiang et al, 2015), and its expression is induced by NRF2 in human cancer cells (Suzuki et al, 2013; Ye et al, 2014).…”