GSE202265
PLTP is a p53 target gene with roles in cancer growth suppression and ferroptosis
The tumor suppressor protein p53 suppresses cancer by regulating processes such as apoptosis, cell cycle arrest, senescence, and ferroptosis.  Whereas numerous p53 target genes have been identified, only a few appear to be critical for the suppression of tumor growth.  Additionally, while ferroptosis is clearly implicated in tumor suppression by p53, few p53 target genes with roles in ferroptosis have been identified.  We have been studying the activity of germline missense variants of p53 that are hypomorphic.  These hypomorphic variants are associated with increased risk for cancer, but they retain the majority of p53 transcriptional function; as such, study of the transcriptional targets of these hypomorphs has the potential to reveal genes that are important for p53-mediated tumor suppression.  Here, we identify PLTP (phospholipid transfer protein) as a p53 target gene that shows impaired transactivation by three different cancer-associated p53 hypomorphs: P47S (Pro47Ser, rs1800371), Y107H (Tyr107His, rs368771578), and G334R (Gly334Arg, rs78378222).  We show that enforced expression of PLTP potently suppresses colony formation in human tumor cell lines.  We also show that PLTP regulates the sensitivity of cells to ferroptosis, which is an iron mediated and lipid peroxide-induced cell death pathway.  Taken together, our findings reveal PLTP to be a p53 target gene that is extremely sensitive to p53 transcriptional function, and which has roles in growth suppression and ferroptosis Overall design: RNA-seq analysis of LCL cells with WT and P47S p53 variant treated with nutlin