RNAN6-MethyladenosineMethyltransferase-Like3PromotesLiverCancerProgressionThroughYTHDF2-DependentPosttranscriptionalSilencingofSOCS2MengnuoChen,LaiWei,Cheuk-TingLaw,FeliceHo-ChingTsang,JialingShen,CarolLai-HungCheng,Long-HinTsang,DanielWai-HungHo,DavidKung-ChunChiu,JoyceMan-FongLee,CarmenChak-LuiWong,IreneOi-LinNg,andChun-MingWongEpigeneticalterationshavecontributedgreatlytohumancarcinogenesis.ConventionalepigeneticstudieshavepredominantlyfocusedonDNAmethylation,histonemodifications,andchromatinremodeling.Recently,diverseandreversiblechemicalmodificationsofRNAshaveemergedasanewlayerofepigeneticregulation.N6-methyladenosine(m6A)isthemostabun-dantchemicalmodificationofeukaryoticmessengerRNA(mRNA)andisimportantfortheregulationofmRNAstability,splicing,andtranslation.Usingtranscriptomesequencing,wediscoveredthatmethyltransferase-like3(METTL3),amajorRNAN6-adenosinemethyltransferase,wassignificantlyup-regulatedinhumanhepatocellularcarcinoma(HCC)andmulti-plesolidtumors.Clinically,overexpressionofMETTL3isassociatedwithpoorprognosisofpatientswithHCC.Function-ally,weprovedthatknockdownofMETTL3drasticallyreducedHCCcellproliferation,migration,andcolonyformationinvitro.KnockoutofMETTL3remarkablysuppressedHCCtumorigenicityandlungmetastasisinvivo.Ontheotherhand,usingtheCRISPR/dCas9-VP64activationsystem,wedemonstratedthatoverexpressionofMETTL3significantlypromotedHCCgrowthbothinvitroandinvivo.Throughtranscriptomesequencing,m6Asequencing,andm6AmethylatedRNAimmuno-precipitationquantitativereverse-transcriptionpolymerasechainreaction,weidentifiedsuppressorofcytokinesig-naling2(SOCS2)asatargetofMETTL3-mediatedm6Amodification.KnockdownofMETTL3substantiallyabolishedSOCS2mRNAm6AmodificationandaugmentedSOCS2mRNAexpression.Wealsoshowedthatm6A-mediatedSOCS2mRNAdegradationreliedonthem6AreaderproteinYTHDF2-dependentpathway.Conclusion:METTL3isfrequentlyup-regulatedinhumanHCCandcontributestoHCCprogression.METTL3repressesSOCS2expressioninHCCthroughanm6A-YTHDF2-dependentmechanism.Ourfindingssugg...
