Effects Of PRMT5 On Prostate Cancer Cell Proliferation And Its Molecular Mechanism

Background: Protein arginine methyltransferase 5(PRMT5)symmetrically dimethylates arginine residues of histone and non-histone substrates,via epigenetic regulation or signaling of target genes Molecular post-translational modifications to regulate a variety of cellular processes.Studies have shown that PRMT5 may play a role in cancer,and its high expression promotes the occurrence and development of human cancer.However,the molecular mechanism of its high expression and the mechanism by which PRMT5 regulates cancer cell proliferation are still largely unknown,and the research of PRMT5 in prostate cancer(PCa)is still controversial.In this paper,firstly,we determined the expression of PRMT5 in PCa by bioinformatics analysis,and analyzed the relationship between PRMT5 and patient prognosis according to clinical data,and analyzed the signaling pathway that PRMT5 affects in PCa,and preliminarily defined PRMT5 in PCa.In addition,we explored its expression and enriched signaling pathways in primary prostate cancer(pri-PCa)and castration-resistant prostate cancer(CRPC)to investigate whether PRMT5 is a target of AR.To better understand the mechanism of action of PRMT5 in PCa,we treated LNCa P and PC3 cells with EPZ015666(PRMT5 inhibitor)and performed transcriptome-level sequencing(RNA-seq)to analyze differentially expressed genes and map to signaling pathways.Finally,in order to intuitively understand the function of PRMT5 in PCa,we used PCa cells DU145 and PC3 cells as models to conduct a series of cell phenotype experiments,and constructed a nude mouse subcutaneous tumor model to explore the role of PRMT5 in vivo.Conclusions:(1)The expression of PRMT5 is up-regulated in PCa tissues and cells according to the analysis of Oncomine and TCGA database,which was further verified by q-PCR;(2)PRMT5 is enriched in Basal cells in prostate tissue and is related to PCa stemness,promote oncogene-related pathways and lead to poor prognosis of patients;(3)Compared with LNCa P,PRMT5 has a more significant effect on PC3 cells similar to stem-like CRPC,and inhibiting PRMT5 enzyme activity converts PC3 from Basal-like to Luminal-like;(4)After PRMT5 is inhibited,LNCa P and PC3 cells exhibit abnormal occurrence of many alternative splicing events(Alternative Splicing Event,ASE),including intron retention(Intron Retention,IR)and exon skipping(Exon skipping,SE)changed the most;(5)There is no difference in the expression levels of PRMT5 in pri-PCa and CRPC-Ad,and it is experimentally confirmed that PRMT5 is not regulated by AR;(6)At the cellular level,we confirm that PRMT5 can promote PCa cells proliferation,stemness,migration,invasion,and PC3 tumorigenesis in vivo.