title: Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression.
abstract: 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, p534KRis severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KRis 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.
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Shang-Jui
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA.
authors.forename: Le
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Avenue, New York, NY 10032, USA. Electronic address: wg8@cumc.columbia.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D000107:Acetylation; D027182:Amino Acid Transport System y+ / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D059447:Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009154:Mutation; D010744:Phosphoric Monoester Hydrolases; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D027182:Amino Acid Transport System y+; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; C118895:SLC7A11 protein, human; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human
keywords: SLC7A11; acetylation; deacetylation; ferroptosis; metabolic regulation; p53; transcription; tumor suppression