RNAediting-dependentepitranscriptomediversityincancerstemcellsQingfeiJiang,LeslieA.Crews,FridaHolm,andCatrionaH.M.JamiesonDivisionofRegenerativeMedicine,DepartmentofMedicine,MooresCancerCenterandSanfordConsortiumforRegenerativeMedicine,UniversityofCalifornia,SanDiego,LaJolla,California92093,USA.AbstractCancerstemcells(CSCs)canregenerateallfacetsofatumourasaresultoftheirstemcell-likecapacitytoself-renew,surviveandbecomedormantinprotectivemicroenvironments.CSCsevolveduringtumourprogressioninamannerthatconformstoCharlesDarwin’sprincipleofnaturalselection.AlthoughsomaticDNAmutationsandepigeneticalterationspromoteevolution,post-transcriptionalRNAmodificationstogetherwithRNAbindingproteinactivity(the‘epitranscriptome’)mightalsocontributetoclonalevolutionthroughdynamicdeterminationofRNAfunctionandgeneexpressiondiversityinresponsetoenvironmentalstimuli.DeregulationoftheseepitranscriptomiceventscontributestoCSCgenerationandmaintenance,whichgovernscancerprogressionanddrugresistance.InthisReview,wediscusstheroleofmalignantRNAprocessinginCSCgenerationandmaintenance,includingmechanismsofRNAmethylation,RNAeditingandRNAsplicing,andthefunctionalconsequencesoftheiraberrantregulationinhumanmalignancies.Finally,wehighlightthepotentialoftheseeventsasnovelCSCbiomarkersaswellastherapeutictargets.Withregardtoevolutioninspecificecologicalniches,Darwinstatedthat“thesamespecies,also,oftenhaveasomewhatmonstrouscharacter…theyoftendifferinanextremedegreeinsomeonepart,bothwhencomparedonewithanother,andmoreespeciallywhencomparedwithallthespeciesinnaturetowhichtheyarenearestallied”(REF.1).Inasimilarsense,cancercellsthatdevelopinspecificmicroenvironmentsrepresentamonstrouscaricatureofnormaldevelopment.Cancerstemcells(CSCs)aretypicallyrarecellswithintumoursthatexploitstemcellproperties,therebyenablingthemtobecomedormant,surviveandregenerateinprotectivemicroenvironments,albeitinaderegulatedmanner(BOX1).TheseCSCsrepresentareservoirofself-sustainingcellsthatgiverisetomanytypesofcancercell.Inco...
