Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Significance

Although it is commonly accepted that p53-mediated cell-cycle arrest, apoptosis, and senescence all serve as major mechanisms of tumor suppression, accumulating evidence indicates that other activities of p53, such as ferroptosis, are also critical for tumor suppression. However, the molecular mechanisms by which p53-mediated ferroptosis operates are not completely understood. In this study, we discovered that p53 can execute ferroptotic cell-death responses by directly activating its target gene SAT1, coded for the spermidine/spermine N ¹ -acetyltransferase 1. These data indicate a regulatory role of p53 in polyamine metabolism and reveal that p53-mediated activation of SAT1 contributes significantly to ferroptotic responses. Thus, p53 may engage multiple metabolic pathways with ferroptotic cell-death responses for tumor suppression.

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 N ¹ -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.