ArticleLncRNAHAND2-AS1promoteslivercancerstemcellself-renewalviaBMPsignalingYanyingWang1,†,PingpingZhu1,†,JianjunLuo2,†,JingWang1,3,†,ZhiweiLiu4,†,WeiWu2,YingDu1,BuqingYe1,DongpengWang2,3,LeiHe4,WeizhengRen4,JianyiWang1,3,XianhuiSun2,3,RunshengChen2,*,YongTian2,3,**&ZusenFan1,3,***AbstractHepatocellularcarcinoma(HCC)isthemostprevalentlivercancer,characterizedbyahighrateofrecurrenceandheterogeneity.Livercancerstemcells(CSCs)maywellcontributetobothofthesepatho-logicalproperties,butthemechanismunderlyingtheirself-renewalmaintenanceispoorlyunderstood.Here,weidentifiedalongnoncod-ingRNA(lncRNA)termedHAND2-AS1thatishighlyexpressedinliverCSCs.HumanHAND2-AS1anditsmouseorthologlncHand2displayahighlevelofconservation.HAND2-AS1isrequiredfortheself-renewalmaintenanceofliverCSCstoinitiateHCCdevelopment.Mechanistically,HAND2-AS1recruitstheINO80chromatin-remo-delingcomplextothepromoterofBMPR1A,therebyinducingitsexpressionandleadingtotheactivationofBMPsignaling.Impor-tantly,interferingwithexpressionofHAND2-AS1byantisenseoligonucleotides(ASOs)andBMPR1AbysiRNAshassynergisticanti-tumorigeniceffectsonhumanizedHCCmodels.Moreover,knockoutoflncHand2orBmpr1ainmousehepatocytesimpairsBMPsignalingandsuppressestheinitiationoflivercancer.OurfindingsrevealthatHAND2-AS1promotestheself-renewalofliverCSCsanddrivesliveroncogenesis,offeringapotentialnewtargetforHCCtherapy.KeywordsBMPsignaling;cancerstemcells;HAND2-AS1;hepatocellularcarci-noma;INO80complexSubjectCategoriesCancer;RNABiology;StemCells&RegenerativeMedicineDOI10.15252/embj.2018101110|Received8November2018|Revised7June2019|Accepted13June2019TheEMBOJournal(2019)e101110IntroductionHepatocellularcarcinoma(HCC),themostcommonprimarylivertumor,isthesecondleadingcauseofcancerdeathworldwidewithasteadyincreaseasaconsequenceofchronichepatitisinfection,metabolicsyndrome,andcirrhosis(Marquardtetal,2015).Inbothadultandpediatricsettings,treatmentsareinadequate,andbettertherapeutictargetsareneeded(Jietal,2009).Newtreatmentsarelikelyfromanimproved...
