NuclearfactoronetranscriptionfactorsasepigeneticregulatorsincancerMitchellFane1,2,LachlanHarris1,AaronG.Smith2,3andMichaelPiper11TheSchoolofBiomedicalSciences,TheUniversityofQueensland,Brisbane,QLD,Australia2SchoolofBiomedicalSciences,InstituteofHealthandBiomedicalInnovationattheTranslationalResearchInstitute,QueenslandUniversityofTechnology,Woolloongabba,QLD,Australia3DermatologyResearchCentre,TheUniversityofQueensland,SchoolofMedicine,TranslationalResearchInstitute,Brisbane,QLD,AustraliaTumourheterogeneityposesadistinctobstacletotherapeuticintervention.Whiletheinitiationoftumoursacrossvariousphysiologicalsystemsisfrequentlyassociatedwithsignaturemutationsingenesthatdriveproliferationandbypasssenescence,increasingevidencesuggeststhattumourprogressionandclonaldiversityisdrivenatanepigeneticlevel.Thetumourmicroenvironmentplaysakeyroleindrivingdiversityascellsadapttodemandsimposedduringtumourgrowth,andisthoughttodrivecertainsubpopulationsbacktoastemcell-likestate.Thisstemcell-likephenotypeprimestumourcellstoreacttoexternalcuesviatheuseofdevelopmentalpathwaysthatfacilitatechangesinproliferation,migrationandinvasion.Becausethedynamismofthisstemcell-likestaterequiresconstantchromatinremodellingandrapidalterationsatregulatoryelements,itisofgreattherapeuticinteresttoidentifythecell-intrinsicfactorsthatconfertheseepigeneticchangesthatdrivetumourprogression.Thenuclearfactorone(NFI)familyaretranscriptionfactorsthatplayanimportantroleinthedevelopmentofmanymammalianorgansystems.Whileallfourfamilymembershavebeenshowntoactaseitheroncogenesortumoursuppressorsacrossvariouscancermodels,evidencehasemergedimplicatingthemaskeyepigeneticregulatorsduringdevelopmentandwithintumours.Notably,NFIshavealsobeenshowntoregulatechromatinaccessibilityatdistalregulatoryelementsthatdrivetumourcelldisseminationandmetastasis.HerewesummarizetheroleoftheNFIsincancer,focusinglargelyonthepotentialmechanismsassociatedwithchromatinremodellingandepigeneticmodulationofgeneexpression.IntroductionEpigenetics...
