RESEARCHOpenAccessRNAN6-methyladenosinedemethylaseFTOpromotesbreasttumorprogressionthroughinhibitingBNIP3YiNiu1,ZiyouLin1,ArabellaWan4,HongleiChen5,HengLiang1,LeiSun1,YuanWang6,XiLi3,Xiao-fengXiong1,BoWei3*,XiaobinWu2*andGuohuiWan1,7*AbstractBackground:N6-methyladenosine(m6A)modificationisthemostpervasivemodificationinmRNA,andhasbeenconsideredasanewlayerofepigeneticregulationonmRNAprocessing,stabilityandtranslation.Despiteitsfunctionalsignificanceinvariousphysiologicalprocesses,theroleofthem6Amodificationinvolvedinbreastcancerisyetfullyunderstood.Methods:Weusedthem6A-RNAimmunoprecipitationsequencingtoidentifythepotentialtargetsinbreastcancer.TodeterminetheunderlyingmechanismfortheaxisofFTO-BNIP3,weperformedaseriesofinvitroandinvivoassaysin3breastcancercelllinesand36primarybreasttumortissuesand12adjuncttissues.Results:WeshowedthatFTO,akeym6Ademethylase,wasup-regulatedinhumanbreastcancer.HighlevelofFTOwassignificantlyassociatedwithlowersurvivalratesinpatientswithbreastcancer.FTOpromotedbreastcancercellproliferation,colonyformationandmetastasisinvitroandinvivo.WeidentifiedBNIP3,apro-apoptosisgene,asadownstreamtargetofFTO-mediatedm6Amodification.Epigenetically,FTOmediatedm6Ademethylationinthe3’UTRofBNIP3mRNAandinduceditsdegradationviaanYTHDF2independentmechanism.BNIP3actsasatumorsuppressorandisnegativelycorrelatedwithFTOexpressioninclinicalbreastcancerpatients.BNIP3dramaticallyalleviatedFTO-dependenttumorgrowthretardationandmetastasis.Conclusions:Ourfindingsdemonstratethefunctionalsignificanceofthem6Amodificationinbreastcancer,andsuggestthatFTOmayserveasanovelpotentialtherapeutictargetforbreastcancer.Keywords:Breastcancer,N6-methyladenosine,FTO,BNIP3,ApoptosisBackgroundBreastcancercontinuestobeaseverethreattowardswomenintheworld.Itisestimatedthatmorethan2.1millionnewcasesofbreastcanceroccurredin2018,causing627,000deathinwomen[1].Withtheadventofmolecularclassificationinbreastcancer,the5-yearsur-vivalrateforpatientsdiagnosedwithlocalizedtumorsreached90%,however,fortho...
