Inhibitory Effect And Mechanism Of Ribavirin On Colorectal Cancer Via Mediating PRMT5

Background: To the best of our knowledge,including our previous research,protein arginine methyltransferase 5(PRMT5)is frequently up-regulated in colorectal cancer and a variety of tumors,which is closely related to the occurrence,development and prognosis of tumors.It is currently a highlight of tumor drug targeted therapy.Ribavirin(RIB),a broad-spectrum antiviral drug,is the only clinically approved drug known to target eukaryotic translation initiation factor 4E(eIF4E),is an anti-viral molecule currently used in hepatitis C therapy.The potential role of RIB via PRMT5 to treat CRC remains largely unexplored.Objective: Here we will focus on the function and epigenetic mechanism of RIB in CRC,and we propose that RIB represents a new therapeutic option for CRC patients.Methods: The role of RIB in CRC was investigated by3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT),colony formation assay and cell cycle analysis.Using established mouse models of colorectal tumorigenesis,including azoxymethane-dextran sulfate sodium(AOM-DSS)model of colitis-associated tumor and tumor cell derived xenograft,we further evaluate the effect of RIB on antitumor activity of CRC in vivo.The effects of RIB on the enzymatic activities of PRMTs including PRMT5 were detected by PRMTs Chemiluminescent Assay Kit.Here we performed the effects of RIB on the enzymatic activities of PRMTs including PRMT5 were detected by PRMTs Chemiluminescent Assay Kit.Meanwhile,we used quantitative reverse transcription-polymerase chain reaction(qRT-PCR)and Western blot experiments to reveal the underlying molecular mechanism on PRMR5 transcriptional/translational regulation,analyzed histone target H3R8me2s/H4R3me2 s,P53 protein and other cancer-related pathways.Results: RIB treatment in CRC cell lines drastically inhibited cell proliferation and colony formation,and suppressed tumorigenesis in mouse model ofcolitis-associated CRC.Mechanistically,RIB treatment significantly induced S phase arrest and cell apoptosis,reduced Cyclin D1 and proliferating cell nuclear antigen(PCNA)levels in vitro,reduced PRMT5 protein levels and the accumulation of symmetric dimethylation of histone 3 at arginine 8(H3R8me2s)and that of histone 4at arginine 3(H4R3me2s).Conclusions: Our results demonstrate the anti-cancer efficacy of RIB in CRC and suggest that the anti-cancer efficacy of RIB may be mediated by downregulating PRMT5 levels and its specific methylation marks,H3R8me2 s and H4R3me2 s.