PLA2G16 is a Mutant P53/klf5 Transcriptional Target and Promotes Glycolysis of Pancreatic Cancer.

PLA2G16 is a member of the phospholipase family that catalyses the generation of lysophosphatidic acids (LPAs) and free fatty acids (FFAs) from phosphatidic acid. In the current study, we explored the functional role of PLA2G16 in pancreatic adenocarcinoma (PAAD) and the genetic/epigenetic alterations leading to its dysregulation. Bioinformatic analysis was performed using data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and the Human Protein Atlas (HPA). Then, PANC-1 and MIA-PaCa-2 cells harbouringTP53mutations were used for cellular and animal studies. Results showed thatPL2G16expression was significantly up-regulated in PAAD tissue and was associated with unfavourable survival.PLA2G16inhibition suppressed pancreatic cell growth in vitro and in vivo and also inhibited aerobic glycolysis. Bioinformatic analysis indicated thatKLF5was positively correlated withPLA2G16expression in PAAD tumours withTP53mutation.TP53orKLF5inhibition significantly reducedPLA2G16expression at both mRNA and protein levels. Dual-luciferase and chromatin Immunoprecipitation-quantitative polymerase chain reaction assays showed that KLF5 directly bound to the PLA2G16 promoter and activated its transcription. Co-immunoprecipitation assay indicated that mutant p53 had a physical interaction with KLF5. Inhibition of mutant p53 impaired the transcriptional activating effects of KLF5. In PAAD cases in TCGA,PLA2G16expression was positively correlated with its copy number (Pearson'sr = 0.51,P < 0.001), but was strongly and negatively correlated with the methylation level of cg09518969 (Pearson'sr = -0.64,P < 0.001), a 5'-cytosine-phosphodiester bond-guanine-3' site within its gene locus. In conclusion, this study revealed a novel mutant p53/KLF5-PLA2G16 regulatory axis on tumour growth and glycolysis in PAAD.