title: Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses.
abstract: Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPR-cas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Shang-Jui
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Dawei
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Bo
authors.initials: B
authors.lastname: Chu
authors.affiliation: Institute for Cancer Genetics, Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032; wg8@cumc.columbia.edu.|Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001093:Arachidonate 15-Lipoxygenase / Q000187:drug effects / Q000378:metabolism; D064113:CRISPR-Cas Systems; D063646:Carcinogenesis / Q000187:drug effects; D059447:Cell Cycle Checkpoints; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D053858:Metabolic Networks and Pathways; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D011073:Polyamines / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D013095:Spermidine / Q000378:metabolism; D013096:Spermine / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D023041:Xenograft Model Antitumor Assays; D000099228:Diamine N-Acetyltransferase
chemical_list: D000123:Acetyltransferases; D001093:Arachidonate 15-Lipoxygenase; D009363:Neoplasm Proteins; D011073:Polyamines; D051736:Proto-Oncogene Proteins c-mdm2; D017382:Reactive Oxygen Species; D013095:Spermidine; D013096:Spermine; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases; D000099228:Diamine N-Acetyltransferase; C515716:ALOX15 protein, human; C497206:MDM2 protein, human; C467728:STUB1 protein, human
keywords: SAT1; ferroptosis; p53; polyamine metabolism; tumor suppression