| FTY720,an FDA-approved oral drug,has been used in the treatment of multiple sclerosis.In recent years,the anti-cancer effect of FTY720 has been drawing much more attentions in the field,but it is still not clear in terms of the mechanism of FTY720mediated tumor suppressive effect.The tumor suppressor p53 coordinates the cellular response to variously exogenous or endogenous stresses by selectively activating or repressing a broad range of downstream target genes,which consequently participates in the regulation of a series of biological processes and contributes to its tumor suppressive functions.In this study,we explored whether the FTY720 participated in the regulation of p53-mediated gene transcription and evaluated the potential roles of FTY720-p53 axis in the modulation of cellular biological processes.In human osteosarcoma U2OS cells that express the wildtype p53,the CRISPR/Cas9 technique was successfully used to generate a p53-knockout(p53-KO)cell line.Control cells or p53-KO cells were treated with or without FTY720 and the transcriptional profiles were then assessed by RNA-sequencing(RNA-seq)analysis.The differentially expressed genes,as well as their potential functions,were annotated by using bioinformatic analysis.Finally,we identified 220 p53-mediated downstream genes in response to FTY720 treatment.These genes were functionally enriched in the regulation of multiple biological processes including negative regulation of platelet activation,cellular response to chemokine,positive regulation of Rho protein signal transduction,multicellular organismal homeostasis,mucin type O-glycan biosynthesis,ECM-receptor interaction,viral protein interaction with cytokine and cytokine receptor.Taken together,our study revealed that FTY720 indeed contributes to the regulation of p5 3-mediated transcriptional profiles and plays an unexpected role in the selective modulation of p53-mediated non-canonical biological processes.These findings implied that the activation of p53 is involved in FTY720-mediated tumor suppressive functions.Thus,our research would provide a new insight into the anti-tumor mechanism of FTY720 via the regulation of p53 signaling pathway. |
