PRMT5 Promotes Cell Proliferation And Invasion Via Repressing Tumor Suppressor Gene ST7 By H4R3 Arginine Methylation In Pancreas Cancer

Background:Pancreatic cancer is(PC)one of the most malignant tumors in the digestive tract.It has the characteristics of occult onset,low resection rate,and the traditional radiotherapy and chemotherapy is not sensitive,and the prognosis is very poor.It is still the focus of the current treatment and research of PC to elucidate the pathogenesis and to explore novel effective treatment methods.Through their ability to catalyze symmetric or asymmetric methylation of histones and non-histone proteins,members of the protein arginine methyltransferase(PRMT)family regulate chromatin structure and expression of a wide spectrum of target genes.Unlike other PRMTs,PRMT5 works in concert with a variety of cellular proteins including ATP-dependent chromatin remodelers and co-repressors to induce epigenetic silencing.Recent work also implicates PRMT5 in the control of growth-promoting and pro-survival pathways,demonstrating its versatility as an enzyme involved in both epigenetic regulation of anti-cancer target genes and organelle biogenesis.These studies not only provide insight into the molecular mechanisms by which PRMT5 contributes to growth control,but also justify targeting PRMT5 therapeutically.Objective:To identify PRMT5 expression in PC and clear the role and molecular mechanism of PRMT5 involved in PC cell proliferation and invasion.Methods:We analyzed PRMT5 protein expression in 87 cases of PC tissues and five PC cell lines.PRMT5 siRNA was employed in PC cell lines.CCK8 assay and Colony formation assays were used to test proliferation ability of PC cell lines.Transwell assay was employed to check the invasion ability of PC cell lines.Cell cycle assay and Flow cytometry were used to test the effects of PRMT5 on the cell cycle and apoptosis of PC cells.ChIP assay indicate if PRMT5 is binding to the promoter of ST7and suppressor it expression by H4R3 arginine methylationResults:We analyzed PRMT5 protein expression in 87 cases of PC tissues and six PC cell lines.We found that PRMT5 expression was upregulated in PC tissue and cell lines.The high expression of PRMT5 was significantly correlated with the vascular accumulation of tumor and the survival period of the patients.(p<0.05).To confirm the biological function of PRMT5 in PC cell lines,PRMT5 siRNA was employed in Miapaca-2 cell line and CFPAC-1 cell line.PRMT5 knockdown by siRNA inhibited cell proliferation and led to cell cycle arrest and loss of cell migratory activity.To explore the molecular mechanism underlying the biological effects of PRMT5,chromatin immunoprecipitation assay was used to identify the target gene regulated by PRMT5.We identified the tumor suppressor ST7 as a key gene silenced by PRMT5 via increasing methylation of histone H4R3 in PC cells.Conclusions:PRMT5 in pancreatic cancer tissue were high expression and overexpression of PRMT5 methylated histones H4R3 to inhibit the expression of ST7,thus promoting the value of pancreatic cancer cell lines,migration and invasion ability.