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REVIEWEpigeneticGeneRegulationbyDietaryCompoundsinCancerPreventionMcKaleMontgomeryandAishwaryaSrinivasanDepartmentofNutritionalSciences,OklahomaStateUniversity,Stillwater,OKABSTRACTTraditionally,cancerhasbeenviewedasasetofdiseasesthataredrivenbytheaccumulationofgeneticmutations,butwenowunderstandthatdisruptionsinepigeneticregulatorymechanismsareprevalentincanceraswell.Unlikegeneticmutations,however,epigeneticalterationsarereversible,makingthemdesirabletherapeutictargets.Thepotentialfordiet,andbioactivedietarycomponents,totargetepigeneticpathwaysincancerisnowwidelyappreciated,butourunderstandingofhowtoutilizethesecompoundsforeffectivechemopreventivestrategiesinhumansisinitsinfancy.Thisreviewprovidesabriefoverviewofepigeneticregulationandtheclinicalapplicationsofepigeneticsincancer.Itthendescribesthecapacityfordietarycomponentstocontributetoepigeneticregulation,withafocusontheefficacyofdietaryepigeneticregulatorsassecondarycancerpreventionstrategiesinhumans.Lastly,itdiscussesthenecessaryprecautionsandchallengesthatwillneedtobeovercomebeforethechemopreventivepowerofdietary-basedinterventionstrategiescanbefullyharnessed.AdvNutr2019;10:1012–1028.Keywords:DNAmethylation,histonemodifications,noncodingRNAs,chemoprevention,bioactivecomponentIntroductionDietaryfactorsaresecondonlytotobaccoaspreventablecausesofcancerinWesterncountries(1).Bothmicronutrientinsufficienciesandmacronutrientexcessareknowncontrib-utorstocancerdevelopmentandprogression,yetworldwidemicronutrientdeficienciespersist,andobesityratesareatanall-timehigh(2).Assuch,alternativediet-basedchemopreventiveapproachesareferventlybeingsought.Theterm“chemoprevention”wasfirstusedin1976inthecontextofworkwithvitaminAandretinoids,anddefinedas“theuseofnaturalorsyntheticagentstoblock,retard,orreversethecarcinogenicprocess”(3).Thus,theideaofutilizingdietarycomponentstopreventcancerdevelopmentisnotanewconcept,butourunderstandingoftheirchemoprotectiveactionsisrapidlyevolving.EpigeneticsisdefinedasheritablemodificationstothegenomethatdonotinvolveachangeinDNAsequence.Byinfluencinggeneexpressionoftheindividual,epige-neticmodificationsdeterminehumanappearance,behavior,stressresponse,diseasesusceptibility,andevenlongevity,Start-upfundsfromOklahomaStateUniversitysupportedthiswork.Authordisclosures:MMandAS,noconflictsofinterest.AddresscorrespondencetoMM(e-mail:mckale.montgomery@okstate.edu).Abbreviationsused:DNMT,DNAmethyltransferase;EGCG,(–)-epigallocatechin3-gallate;HAT,histoneacetyltransferase;HDAC,histonedeacetylase;lncRNA,longnoncodingRNA;miRNA,microRNA;ncRNA,noncodingRNA;PEITC,phenethylisothiocyanate;RISC,RNA-inducedsilencingcomplex.givingrisetotheindividualphenotype.Assuch,epigeneticmechanismsareessentialforregulatingnormalphysiologicprocesses,andaberrantepigeneticalterationshavebeenimplicatedinthepathologyofnumerousdiseases.Unlikegeneticinheritance,epigeneticmarksareinfluencedbythingssuchaslifestyle,environment,andnutritionalstatus.Thus,targetingtheepigenometotreatandpreventdiseaseisapromisingtherapeuticapproach.EpigeneticcontrolofgeneexpressionismediatedviaDNAmethylation,histonemodifi-cations,andnoncodingRNAs,andimportantlyeachofthesecontrolpointscanbetargetedbydietarycomponents.CurrentStatusofKnowledgePart1:overviewofepigeneticregulationDNAmethylation.DNAmethylationinvolvesthecovalenttransferofamethylgrouptoDNAbyDNAmethyltransferases(DNMTs)(4).MostDNAmethylationoccurswithinaregioninwhichacytosinenucleotideisattachedtoaguaninenucleotideviaaphosphatelinkage,whichisknownasaCpGsite(5).DenserepeatsofCpGnucleotides,calledCpGislands,occurthroughoutthegenome,althoughthemajorityofmethylatedCpGislandsareassociatedwithinprotein-codinggenes(4).MethylationofCpGislandswithinthepromoterregionofageneistypicallyinverselyassociatedwithtranscriptionof1012CopyrightCAmericanSocietyforNutrition2019.Allrightsreserved.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.org/licenses/by/4.0/),whichpermitsunrestrictedreuse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.AdvNutr2019;10:1012–1028;doi:https://doi.org/10.1093/advances/nmz046.Downloaded from https://academic.oup.com/advances/article/10/6/1012/5491277 by guest on 25 May 2023
thatgeneduetobindingofmethyl-CpGbindingproteins,whichsubsequentlyblocktranscription(6).Duringcellularreplication,DNAmethylationpatternsaremaintainedandpassedonfromtheparentalstrandofDNAviatheenzymaticactionofDNMT1(7).Incontrast,DNMT3AandDNMT3BarereferredtoasdenovomethyltransferasesbecauseoftheirabilitytoproducenewDNAmethylationmarkswithinCpGdinucleotides,whichareespeciallyimportantinearlydevelopment(6).AclassicexampleofDNAmethylationandepigeneticregulationisthediet-modifiedphenotypeoftheagoutigene,whichregulatescoatcolorandweightinmice.Whenthegeneisunmethylated,andthusactivelybeingtranscribed,theresultingphenotypeisanobesemousewithayellowcoat.However,thisactivationcanbesuppressedbypromotingDNAmethylationviaamethyl-richdiet.Importantly,maternalsupplementationwithamethyl-richdietissufficienttorepressagoutioverexpressioninoffspringaswell(8).Changesinbothglobalandgene-specificDNAmethylationpatternscaninfluencecancerdevelopment.Histonemodifications.Histonesaretheprimarycomponentsofchromatin,theDNA-proteincomplexthatmakesupchromosomes.Withinthenucleus,DNAwindstightlyaroundanoctamerofhistones,andassuchhistonemodificationscaninfluencechromatinarrangementandDNAtranscription(9).Histonescanbemodifiedbyacetylation,methylation,phosphoryla-tion,ubiquitination,ADP-ribosylation,andbiotinylationoftheirN-terminalhistonetails(6).Histoneacetylationisconferredbyhistoneacetyltrans-ferases(HATs),whichtransferacetylgroupsontotheε-aminogroupofalysineresiduewithinthehistonetail.Subsequently,thechargeofthelysineisneutralizedandtheinteractionbetweenthehistonetailandDNAisweakened,leadingtochromatinrelaxation,andgenetranscription(10).IncontrasttoHATs,histonedeacetylases(HDACs)removeacetylgroupsfromlysinesandrestorethepositivechargeonthehistonetail,andaregenerallythoughtofastranscriptionalrepressors.Histonephosphorylationanddephosphorylationofserines,threonines,andtyrosineswithinhistonetailsismediatedbyhistonekinasesandphosphatases,respectively(11).Likeacetylation,histonephosphorylationalsoaltersthechargeofthehistoneprotein,therebyalteringthestructureofthechromatinenvironment(6).Methylation,ontheotherhand,doesnotchangetheionicchargeofthehistoneprotein.Rather,methylationoflysineandarginineresidueswithinhistonetailsinfluencesgenetranscriptionthroughtherecruitmentandbindingofeffectormolecules(11).Histoneubiquitinationislesswellunderstoodthantheotherhistonemodifications,butwedoknowthatitistightlyregulatedbyspecifichistoneubiquitinligasesanddeubiquitinatingenzymes.Moreover,althoughmanyproteinsaretargetedforubiquitination,histonesarebyfarthemostubiquitinatedproteinsinthenucleus,andthishelpsthemperformcriticalrolesincludingtranscription,maintenanceofchromatinstructure,andDNArepair(12).Assuch,aberranthistonemodificationshavebeenimplicatedinallstagesofcancerdevelopment.NoncodingRNAs.EpigeneticcontrolcanalsoberegulatedvianoncodingRNA(ncRNA)-basedmechanisms.Generally,ncRNAsaresubdividedbasedonsizeintolong(>200nt)orsmallncRNAs.SmallncRNAsarealsofurthercategorizedintomicroRNAs(miRNAs),smallinterferingRNAsorPIWI-interactingRNAs.ThousandsofmiRNAandlongnoncoding(lncRNAs)areencodedwithinthehumangenome,andareoftenexpressedinacell-type-,tissue-,anddisease-specificmanner(13).Together,theseclassesofRNAspeciesmakeupthemorethantwo-thirdsofthehumangenomethatistranscribedbutnottranslatedintoproteins,althougheachplaysignificantrolesinregulatingtheexpressionandfunctionofprotein-codinggenes.Tothisend,theepigeneticnatureofmiRNAregulationisreciprocalinnature.miRNAtranscriptioncanbemodulatedbybothDNAmethylationandhistonemodifications,andmiRNAthemselvescan,inturn,regulatecrucialenzymesthatdriveepigeneticremodeling(14–17).ToregulategeneexpressionmiRNAmustfirstassem-bleintoamultiproteinRNA-inducedsilencingcomplex(RISC).Onceassembled,theboundmiRNA/RISCcomplexisthencompetenttotargetagivenmRNAbasedontherecognitionoftargetsequenceswithinagivenmRNA.TheboundmiRNA/RISCcomplexnegativelyregulatestargetgeneexpressionviatranscriptdegradationortranslationalinhibition,oracombinationofboth(18).lncRNAs,ontheotherhand,mayregulategeneexpressionthoughmultiplemechanisms:byfunctioningassignalsfortranscriptioninitiation,byactingasdecoysfortitratingtranscriptionfactorsandmiRNA,byservingasguidesforchromatin-modifyingenzymes,orbyservingasscaffoldsfortheformationofribonuecleoproteincomplexes(19,20).Becauseoftheirdynamicexpressionandfunctionalversatility,ncR-NAshavebeendemonstratedtocontributetoanumberofcriticalphysiologicprocesses,andtheirdysregulationhasbeenimplicatedinthepathogenesisofmanydiseasestates(21).Withregardstohumancancerdevelopmentandprevention,miRNAandlncRNAsarethebest-characterizedncRNAs,witheachhavingestablishedoncogenicandtumor-suppressivefunctions(22–24).Part2:dietaryepigeneticregulatorsincancerpreventionCancerrisk,andepigeneticmarkerssuchasDNAmethy-lationandhistoneacetylation,areshapedbybothgeneticpredispositionandenvironmentalinfluences.Assuch,epi-geneticmarkerscanprovidecriticaletiologicinsightintohowgeneticcodeistranslatedintobiologicalaction,andthusepigenetic-basedtherapiesprovideopportunitiesforthedevelopmentofprecisionmedicine.Indeed,epigeneticbiomarkershavedemonstratedutilityincancerriskpredic-tion,diagnostics,treatment,andevenpredictingthetreat-mentresponse(25–27).Oncecancerhasdeveloped,however,Dietaryepigeneticregulatorsincancer1013Downloaded 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FIGURE1Overviewofthecomplexityandoverlapofdiet-basedepigeneticregulatorymechanisms.BioactivecomponentsofdietarysourcescanalterDNAmethylationby(A)servingasmethyldonorsforDNAmethylation,or(B)preventingDNAmethylationbyactingasDNMTinhibitors.DecreasedDNAmethylationpromotestranscriptionofgenes,suchasHATs.(C)DietarymiRNAmodulatorscaneitherupregulateordownregulatemiRNAexpression.miRNAcontrolsgeneexpressionbybindingtotargetmRNAsandsubjectingthemtotranslationalrepressionortranscriptdegradation.DegradationofHATtranscriptswoulddecreasehistoneacetylation,resultingintranscriptionalrepressionviachromatincompaction.(D)Bypreventinghistonedeacetylation,dietaryHDACinhibitorscanpromotehistoneacetylationandchromatinrelaxation,therebymakingDNAmoreaccessibletotranscriptionfactors.(E)DietarycomponentscanalsomodulatethetranscriptionoflncRNAs,whichcantheninfluencegeneexpressionbyactingasdecoysformiRNAandtranscriptionfactors.DNMT,DNAmethyltransferase;HAT,histoneacetyltransferase;HDAC,histonedeacetylase;lncRNA,longnoncodingRNA;miRNA,microRNA.thegeneticdiversityandcomplexityofmanycancersoftenrenderstreatmentsineffective.Thus,identifyingeffectivestrategiesforchemopreventionisnecessaryforreducingtheglobalburdenofcancer.Chemopreventioncanbebroadlydefinedtoincludearangeofapproachessuchasavoidanceofcarcinogenexpo-sure(primaryprevention),blocking,slowing,orreversingcancerprogression(secondaryprevention),andsubduingorremovingprecancerouslesions(tertiaryprevention).Thereversiblenatureofepigeneticmodificationsmakesthemdesirabletargetsforchemoprevention.Interestingly,bioactivecomponentsfrombothessentialandnonessentialdietarycompoundscanactasepigeneticregulatorsbyinflu-encingDNAmethylation,histonemodifications,andncRNAexpressionandfunction(Figure1).Itisnotsurprising,then,thatbioactivecomponentsfromdietarysourceshavebeensuggestedtohaveefficacyinprimary,secondary,andtertiarycancerpreventionstrategies.Harnessingthechemopreventivepowerofsuchdietaryagentsiscomplicated,however,becausetheycanbemetabolizedintomanyuniquebioactivemetabolites,whichoftenhaveoverlappingimpactsonepigeneticcontrolmechanisms.Forexample,glycosinolates,whicharefoundincruciferousvegetables,canbebrokendownintoisothiocyanate(sulforaphane),phenethylisothiocyanate(PEITC),indole-3-carbinol,and3,3-diindolylmethane—allofwhicharechemopreventive,andeachofwhichcaninfluenceDNAmethylation,histonemodifications,andmiRNAexpression(28).Furthermore,toelicittheseepigeneticalterations,andexertitschemopreventiveactions,theresultantbioactivemetabolitehastofirstentercirculationatsufficientconcentrationssuchthatitcanactuallyreachitstargettissue.Thus,theeffectivenessofagivendietarycom-poundisdependentuponthebioavailabilityofthebioactivecomponent.Bioavailability,andsubsequentefficacy,are,howeveralsoaffectedbytheintrinsicgenetic,epigenetic,andenvironmentalinfluencesoftheindividual.Themixedresultsofthepreclinicalandclinicalstudiesdescribedbelowfurtherhighlightthecomplexityofdevelopingpopulation-leveldietaryinterventionchemopreventivestrategies.ChemopreventivepotentialofdietaryDNMTinhibitors.VariationsinthedegreeorsiteofDNAmethylationcanleadtodisruptionofchemoprotectivecellularprocessingleadingtotumorinitiationandprogression.Indeed,aberrantDNAmethylationpatternsarehallmarksofmanytypesof1014MontgomeryandSrinivasanDownloaded from https://academic.oup.com/advances/article/10/6/1012/5491277 by guest on 25 May 2023
cancers.Forexample,globalhypomethylationislinkedtochromosomalinstability,whereaspromoterhypermethyla-tionisassociatedwithgenesilencingoftumorsuppressorsincancers(29,30).Substantialevidencesuggeststhattheanticancerpropertiesofmanybioactivefoodcomponentsmay,atleastinpart,beattributedtotheircapacitytoinfluenceDNAmethylationpatterns.Deficienciesinzincandselenium,aswellasexcessretinoicacid,havebeenshowntoleadtoglobalhypomethylation,andareassociatedwithincreasedcancerrisk(30).DietarycomponentscanalsoinfluenceDNAmethylationpatternsbyprovidingsubstratesandactingascofactorsthatarenecessaryfor1-carbonmetabolism.Theavailabilityoftheuniversalmethyldonor,S-adenosylmethionineisdeterminedby1-carbonmetabolism,andiscriticalforproperDNAandhistonemethylationcontrol.Nutrientsinvolvedinthe1-carbonmetabolismpathwayincludevitaminsB-6,B-12,folate,riboflavin,betaine,andcholine,aswellastheaminoacidsmethionine,cysteine,serine,andglycine(6).DietaryinsufficienciesinanyoneofthesenutrientscanleadtoglobalDNAhypomethylation,viadisruptionofthispathway(30).DietaryagentscanalsoinfluencetheenzymaticactivitiesofDNMTs(30).Aspromoterhypermethylationoftumorsuppressorgenesiscommoninmanycancers,DNMTinhibitorsarepromisingagentsforepigenetictherapy.TwosyntheticDNMTinhibitors,azacytidineanddecitabine,arealreadyFDAapprovedforthetreatmentofmyelodysplasticsyndromeandacutemyeloidleukemia(26).However,thepleiotropicmoleculareffectsandsystemictoxicityeventsassociatedwithpharmacologicDNMTinhibitorsprecludestheiruseasaprimarypreventativestrategyinhealthyindividuals.Thus,theidentificationofdiet-derivedDNMTinhibitorsandtheirefficacyaschemopreventiveagentshasreceivedmuchattention.Dietarypolyphenols,particularly(–)-epigallocatechin3-gallate(EGCG)fromgreentea,andgenistein,asoyisoflavone,areperhapsthemostwell-studieddietaryDNMTinhibitors,althoughmanyothershavealsobeenidentified(Table1).EGCGandgenisteinexerttheiranticanceractivityviadirectinhibitionofDNMT1,whichreactivatesmethylation-silencedtumorsuppressorssuchasCDKN2AandO6-methylguanine-DNAmethyltransferase(31,32).BothEGCGandgenisteinhavebeendemonstratedtoeffectivelydetercarcinogenesisinanimalmodels(33,34).However,epidemiologicdataregardingtheanticancerprop-ertiesofEGCGandgenisteininhumanshasbeenmixed(35,36).Unfortunately,early-phaseclinicaltrialshavenotyieldedmuchmorepromisingresults.Inarandomized,placebo-controlledstudy,dailyintakeof400mgEGCGdidnotreducethelikelihoodofprostatecancerinmenwithhigh-gradeprostaticintraepithelialneo-plasiaoratypicalsmallacinarproliferation(oracombinationofboth)(37).Similarly,a4-mointerventiontrialwithresveratrol,whichalsohasDNMTinhibitorproperties,didnotreduceprostatesizeandconcentrationsofprostate-specificantigen(PSA)inmenwithmetabolicsyndrome(38).Thehighestdoseofresveratrol(1000mg)didsignificantlydecreaseserumconcentrationsofandrogenprecursors,however,suggestingalengthierinterventiontimemayhavehadamorepositiveimpact(38).Conversely,arandomizedtrialofsoyisoflavonesupplementationnotonlydidnotreducebreastcancerriskinwomen,butitincreasedbreastepithelialproliferationinpremenopausalwomen(39).Thesuggestionthatsoyexposuremaybemorebeneficialearlierinlifecouldhelpexplainthesenullandsomewhatconflictingfindings(40).Moreover,noneoftheaforementionedstudiesmeasuredtheimpactoftheirdietaryinterventionsonepige-neticmarks,anditisthereforedifficulttodrawconclusionsregardingtheireffectivenessasepigeneticregulatorsinthisTABLE1ChemopreventiveactionsofdietaryDNMTinhibitors1BioactivecomponentSourceTargetAnticancereffectsTypeofcancerModelsystemReferenceApigeninFruitsandvegetablesNFE2L,DNMT1,DNMT3A,↓ViabilitySkincancerCelllines31,42CurcuminTurmericDNMT1,CDKN2B,NEUROG1,NFE2L2↓Proliferation↑ApoptosisAcutemyeloidleukemia,prostatecancerCelllines,mousexenografts43–45DaidzeinSoyBRCA1,GSTP1,EPHB2↓ProliferationProstatecancerCelllines46,47EGCGGreenteaRECK,CDKN2A,TERT↓Invasiveness↓Proliferation↑ApoptosisSquamouscellcarcinoma,coloncancer,breastcancerCelllines48–50GenisteinSoyGSTP1,CDKN1A,RARB,CDKN2AMGMT,BTG3↓Proliferation↓TumorigenesisBreastcancer,prostatecancerCelllines,humanprostatectomies51–54LycopeneTomatoesGSTP1↓ProliferationBreastcancerCelllines52ResveratrolStilbenesDNMT3B,PTEN↓ProliferationBreastcancerACIrats,celllines55,56SulforaphaneCruciferousvegetablesNFE2L2,TERT,DNMT1,DNMT3A↓Proliferation↑ApoptosisProstatecancer,breastcancerCelllines57–591BRCA1,BRCA1DNArepairassociated;BTG3,BTGantiproliferationfactor3;CDKN1A,cyclin-dependentkinaseinhibitor1A;CDKN2A,cyclin-dependentkinaseinhibitor2A;CDKN2B,cyclin-dependentkinaseinhibitor2B;DNMT1,DNAmethyltransferase1;DNMT3A,DNAmethyltransferase3A;DNMT3B,DNAmethyltransferase3B;EGCG,(–)-epigallocatechin3-gallate;EPHB2,EPHreceptorB2;GSTP1,glutathioneS-transferaseπ1;MGMT,O6-methylguanine-DNAmethyltransferase;NFE2L2,nuclearfactor,erythroid2–like2;PTEN,phosphataseandtensinhomolog;RARB,retinoicacidreceptorβ;RECK,reversion-inducingcysteine-richproteinwithkazalmotifs;TERTtelomerasereversetranscriptase.Dietaryepigeneticregulatorsincancer1015Downloaded 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regard.Althoughitisworthnotingthatsecondaryandtertiaryprostatecancerpreventioneffortswithgenistein,aswellasotherdietaryDNMTinhibitorssuchascurcumin,catechin,epicatechin,lycopene,andquercetin,haveyieldedsomemorepromisingclinicaloutcomes(41).Onereasoninterventiontrialsmaynotsupportepidemiologicstudiesisbecauseinterventiontrialsoftenadministersingle,highdoses,whichdonotmimicthesmallamountsofbioactivecomponentsthatpeopleconsumedailyaspartofamixeddiet.Futureresearchshouldassessdietarypatternsratherthansingledietarycomponents,payingparticularattentiontohowtimingofdosingmightinfluencebioavailabilityandefficacy.Inaddition,manycancershaveaverylonglatencyperiod,thustheinterventioninthetrialsdescribedabovemayhaveoccurredtoolateinthecancercontinuum,andearly-lifeinterventionsmaybemoreeffective.Epidemiologicdatasuggestthatadultdiseaseriskisassociatedwithnutrientexposuresearlyinlife,andfindingsfromtheDutchHungerWingerstudieshavedemonstratedtheimportanceofepige-neticimprintingintheselifelongphenotypicconsequences(60).Maternalobesityandinuteroepigeneticreprogram-mingarealsoassociatedwithincreasedriskofsomecancers,particularlybreastandcoloncancers(61).Paternalobesitycanalsonegativelyaffectoffspringinsulin-likegrowthfactor2(IGF2)methylation,andthesetypesofepigeneticmarkerscanpersistthroughouttheirlifetime(61,62).Inarecentstudy,however,dietarysupplementationwithDHAduringpregnancycouldpotentiallymodulatesomeoftheadverseeffectsofmaternaloverweightandobesitybyinfluencingIGF2methylation(63).Thus,dietary-basedepigeneticcan-cerpreventionneedstobethoughtofnotjustonthescaleofthecancercontinuum,butalongthecontinuumofalifespan.Inadditiontobioavailability,dosing,andtimingofexpo-suretopotentialdietarychemopreventiveagents,theexistingDNAmethylationpatternsoftheindividualmayalsoinflu-encetheresponsetoabioactivefoodcomponent(30).Forexample,pretreatmentwiththepharmacologicDNMTin-hibitor,decitabine,increases1,25-dihydroxycholecalciferol-induceddifferentiationinseveralmixed-lineageleukemiacelllines(64).DNAmethylationstatuscanalsoaffectthecellularresponsetoHDACinhibitortreatment,indicatingareciprocalrelationexistsbetweentheepigenomeoftheindividualandtheepigeneticefficacyofbioactivedietarycomponents(65).Therefore,itisimportanttoconsidertheinfluenceofagivenbioactivedietarycomponentwithinthecontextoftheentirediet.ChemopreventivepotentialofdietaryHDACinhibitors.Posttranslationalmodificationsofhistonesarecriticalforcontrollingmanycellularprocesses,suchasgeneexpression,aswellasDNAreplicationandrepair,andthusaberranthistonemodificationshavebeenlinkedtoeachstageofcarcinogenesis.Indeed,ofthe>60differenthistoneresiduesinwhichmodificationshavebeendescribed,manyhavenowbeenlinkedtocancer(98).Becauseofthesignificantcontributionoftheseso-calledhistone“onco-modifications”tothehallmarksofcancer,HDACinhibitorshavebeensoughtafterfortheirclinicalutility.FourHDACinhibitorsarealreadyFDAapprovedforthetreatmentsoflymphomaandmultiplemyeloma.However,theirpleiotropicimpactongeneexpression,andlackofefficacyinsolidtumorshasledtothepursuitofnovelHDACinhibitorsandtheirutilityinchemopreventioninsteadofchemotherapy.ManydietaryHDACinhibitorshavenowbeenidentified,andtheirchemotherapeuticandchemopreventiveefficacyhasbeenestablishedbothinvitroandinanimalmodels(Table2).Sofarevidenceoftheirchemoprotectiveefficacyinhumansislimiting,butsomeearlystageclinicaltrialsarepromising.Allylderivativesfromgarlichavebeenshowntoin-ducehistoneacetylationinvarioushumancancercells.ThemostpotentallylderivativewithregardstoHDACinhibitionisallylmercaptan,whichexertsitsanticancerpropertiesinvitroviathehyperacetylationofCDKN1A,whichsubsequentlyincreasesCDKN1Ageneexpressionandpromotescellcyclearrest(66).Inpreclinicalstudiesthereportedmechanismsofactionofgarlic-derivedcompoundsforcancerpreventionandtreatmentaremuchmoredi-verse,andrangefrominducingapoptosisandautophagytoinhibitingangiogenesisandproliferation(99,100).Arandomizedcrossoverfeedingtrialinhumansdemonstratedthatasinglemealofraw,crushedgarlicinfluencestheexpressionofmultipleimmunity-andcancer-relatedgenes,suggestingthebioactivityofgarlicismultifaceted(101).However,inarandomized,double-blindclinicalinterventionstudy,7yofgarlicsupplementationdidnotreducetheincidenceofprecancerousgastriclesionsorgastriccancerinsubjectsathighriskforgastriccancer(102).Thiscouldpotentiallybeexplainedbecausethepopulationgroupwasalreadyhighriskforgastriccancer,butthewidespreadutilityofgarlicsupplementationwilllikelynotbeabletobeutilizeduntilthemechanismsofactionaremorefullyunderstood.DietaryisothiocyanateshavealsobeenshowntomediateanticanceractivitiesviatheirHDACinhibitoryproperties(103).Isothiocyanates,suchassulforaphane,arethebiologi-callyactivederivativesofglucosinolates,whichareabundantincruciferousvegetables.InpreclinicalstudiessulforaphanehasbeenreportedtoinduceDNAdamageincoloncancercells,andtoinhibittumorgrowthinmice(104,105).Inhumans,increasedcruciferousvegetableconsumptionhasbeenassociatedwithdecreasedriskofcancerdevelopment,likelyviaHDACinhibition(106).Inanevaluationofbaselinedataofwomenwhohadabnormalmammogramfindingsandwerescheduledforbreastbiopsy,totalcruciferousvegetableintakewasassociatedwithdecreasedcellproliferationinbreastductalcarcinomainsitutissue(107).Thissamecohortofwomenwasthenrandomizedinadouble-blindcontrolledtrialtoconsumeaplaceboora250mgbroccoliseedextract3times/dfor2–8wk(108).Althoughcirculatingsul-foraphanemetaboliteswerestatisticallyincreasedinthetreatmentgroupcomparedwiththeplacebo,supplementa-tiondidnotproducemeasurablechangesinbreasttissue1016MontgomeryandSrinivasanDownloaded 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TABLE2ChemopreventiveactionsofdietaryHDACinhibitors1BioactivecomponentSourceTargetAnticancereffectsTypeofcancerModelsystemReferenceAllicin,allylmercaptan,diallyldisulfideGarlicCDKN1A↓Proliferation↓AngiogenesisColoncancer,erythroleukemia,livercancer,prostatecancerCelllines66–69ApigeninFruitsandvegetablesCDKN1A↑Apoptosis↓ProliferationProstatecancerCelllines,mousexenografts42,70ButyrateSolublefibersCDKN1A↑Apoptosis↓ProliferationColoncancerCelllines,ratcarcinogen–inducedcoloncancer71–74CurcuminTurmericDLEC1,NFKB1↑Apoptosis↓Proliferation↓TumorigenesisColoncancer,leukemiaCelllines75–77DaidzeinandgenisteinSoyCDKN1A,CDKN2A,ESR2,BTG3↓ProliferationProstatecancer,renalcancerCelllines53,54,78EGCGGreenteaGSTP1,CDKN1A,CDKN2A↓ProliferationCervicalcancer,prostatecancer,skincancer,breastcancerCelllines79–82Indole-3carbinoldiindolylmethaneCruciferousvegetablesCDKN1,CDKN1B↓Inflammation↑Apoptosis↓ProliferationColoncancer,prostatecancer,breastcancerCelllines,mousexenografts83–85PiceatannolBerries,redgrapesHDAC4,HDAC5↑Apoptosis↓Proliferation↓InflammationMultipletypesRenalfibrosismousemodel,celllines86,87QuercetinApples,darkcherries,berriesSIRT1,FASLG↑Apoptosis↓Proliferation↓Angiogenesis↓InvasivenessHepatocellularcarcinoma,leukemiaCelllines,hamsterbuccalpouchtumors88–90ResveratrolStilbenesTP53,SIRT1↑Apoptosis↓ProliferationProstatecancer,hepatoblastomaCelllines91–93SulforaphaneCruciferousvegetablesCDKN1A,TERT,DEFB4A↑Apoptosis↓Proliferation↑ImmunereponseProstatecancer,colorectalcancer,breastcancerCelllines,mousexenografts,humansubjects57,94–971BTG3,BTGantiproliferationfactor3;CDKN1A,cyclin-dependentkinaseinhibitor1A;CDKN2A,cyclin-dependentkinaseinhibitor2A;DEFB4A,defensinβ4A;DLEC1,DLEC1cilia-andflagella-associatedprotein;EGCG,(–)-epigallocatechin3-gallate;ESR2,estrogenreceptor2;FASLG,Fasligand;GSTP1,glutathioneS-transferaseπ1;HDAC4,histonedeacetylase4;HDAC5,histonedeacetylase5;NFKB1,nuclearfactorκBsubunit1;SIRT1,sitruin1;TERT,telomerereversetranscriptase;TP53,tumorprotein53.biomarkers(108).Inasimilarstudyinvestigatingthechemo-preventivepotentialofsulforaphaneinmen,supplementa-tionwith200μmol/dofsulforaphane-richextractsfor20wkdidnotreducePSAby≥50%,whichwastheprimaryend-pointofthestudy(109).Thestudydesignsmakeitdifficulttodeterminewhetherthenegativeresultswerebecauseofinsufficientdosingorinsufficientduration,orboth,sofuturestudieswillbeneededtodetermineifdietarysulforaphaneregimensmightbeusefulchemopreventionstrategies.Additionally,thediscrepanciesobservedbetweenepi-demiologicdataofcruciferousvegetableintakeandsul-foraphanesupplementationmayalsobeattributedtodif-ferencesinbioavailability.Sulforaphaneisformedbythehydrolysisofitsglucosinolateprecursor,glucophanin,bytheplantenzymemyrosinase,whichisactivatedbydamagetotheplanttissuethatoccursduringchewing(110).Sulforaphaneabsorptionislowerinadultsconsumingglucoraphaninsupplementsthanfreshbroccolisprouts,butthiscanbeimprovedwhenthesupplementsareconsumedwithasourceofactivemyrosinase(111,112).Treatmentofglyophanin-richbroccoliextractswithmyrosinasepriortosupplementationhasalsobeendemonstratedtoen-hancesulforaphanebioavailability(113).Furthermore,arecentstudyalsoreportedthatsubjectsconsumingtwo100-μmoldosesofsulforaphanecontainingbroccoliextract12hapartretainedhigherplasmasulforaphanemetaboliteconcentrationsthansubjectsconsumingone200-μmoldoseevery24h(110).Unfortunately,althoughmostdatasupporttheuseofwhole-foodstrategiesindietarychemopreventionefforts,limitationsinavailability,andvariationsinbioactivecon-tentofwhole-foodsourcesoftennecessitatetheuseofsupplementsinclinicaltrialstodeliverconsistentdosesofthebioactivecomponents.Thefindingsdescribedabove,however,highlighttheimportanceofconsideringboththesourceandthedosingregimenofdietarysupplementsinthedevelopmentofeffectivechemopreventionstrategies.Tobeaneffectivechemopreventiveagent,sufficientconcentrationsofthebioactivecompoundsmustactuallyreachthetargettissue.Inthecaseofcurcumin,whichalsoexhibitsHDACDietaryepigeneticregulatorsincancer1017Downloaded from https://academic.oup.com/advances/article/10/6/1012/5491277 by guest on 25 May 2023
inhibitoryproperties,butpoororalbioavailability,investiga-torshavealsoexplorednanoformulations,bioenhancers,andsyntheticanalogstoincreaseitssolubilityandstabilityandimprovedeliverytotargettissues(114).Promisingresultswithsyntheticanalogs,suchasincreasedconcentrationsofbioactivecurcuminmetabolitesintargettissues,warrantfurtherinvestigationintotheirchemopreventiveefficacy.Althoughmanychallengesremaintobeovercome,thepowerfulepigeneticregulatorycapacityofdietaryHDACinhibitorsunderscorestheirpromisingchemopreventivepotential.Bytargetinghistones,HDACinhibitortreatmentinfluenceschromatinstructureandaffectsgeneexpressionatmanylevels,andthusHDACinhibitorscaninfluencemanydiversecellularfunctions,suchasinducingapoptosis,disruptingcellulargrowthanddifferentiation,andinhibit-ingangiogenesis(Table2).Nonhistoneproteins,suchastranscriptionfactorsandmetabolicenzymes,canalsobetargetedforacetylation,andmanyoftheseareimportantinchemoprotectivecellularprocesses(103).However,duetotheirlargenumberoftargets,andinherentpleiotropicnature,thewidespreaduseofHDACinhibitorswarrantsacautionaryapproach(65).Furthermore,HDACinhibitorefficacycanbeinfluencedbyavarietyofpre-existingfactors,includingcurrentgenomeacetylationstatus,age,environmentalexposures,lifestyle,andevenunderlyinginflammation(65).Thus,abetterunderstandingofthedivergentandcell-type-specificeffectsofdietaryHDACinhibitors,andtheidentificationofroutestoimprovetheirsystemicbioavailabilitywillbenecessarybeforetheirtherapeuticefficacycanbefullyrealized.ChemopreventivepotentialofdietarymodulatorsofncRNAs.ncRNAshavebeenshowntoregulatenearlyallbiologi-calprocesses,andbysilencingoncogenesandupregulat-ingtumorsuppressorgeneexpressionbothlncRNAsandmiRNAscancontributetocancerinitiation,promotion,andprogression.Forexample,themiRNA-34familyissignificantlyupregulatedbythetumorsuppressorTP53,andhelpsmediatecellcyclearrestandapoptosisbyre-pressingtargetssuchascyclinD1andBCL2apoptosisregulator(115,116).Likewise,thelncRNALOC285194,isalsoregulatedinaTP53-dependentmanner,anddisplaystumor-suppressivefunctions(19).Contrarily,thelncRNAHOXtranscriptantisenseRNA(HOTAIR)isupregulatedinnumeroustypesofcancersandisinsteadadriverofmalignancy(117).Thus,utilizationofdietaryagentsthatcanpromoteanticarcinogenicncRNAexpression,orrepresstheirpro-oncogenicfunctions,isadesirablecancer-preventativeapproach.ResearchdemonstratingtheutilityofdietaryinterventionstotargetlncRNAsislimiting,butextensiveevidenceexistssupportingdietary-basedmiRNAtargetingforcancerprevention(Table3).Althoughthemajorityofresearchsupportingthisideahasbeeninvitroandinanimalmodels,promisingearly-stageclinicaltrialsarenowunderway.Asmentionedabove,PEITCisabreakdownproductofglucosinolates,agroupofbioactivesulfur-containingcompoundsabundantincruciferousvegetables.PEITChasbeenshowntoexertanticancereffectsbyinfluencingbothDNAmethylationandhistonemodifications,andmorerecently,miRNA(118).InprostatecancercellsPEITCtreat-mentupregulatesmiR-194expression,whichsubsequentlydecreasesinvasivecapacitybytargetingbonemorphogenicprotein1anddownregulatingtheexpressionofmatrixmetalloproteinases(119).ThesefindingssuggestthatPEITCtreatmentcouldbeusedtodecreasetumoraggressivenessandpreventmetastasis.Idealcancerpreventativeagents,however,wouldworkattheinitiationphaseofcancerprogressiontopreventonsetofthediseaseentirely.Inamousemodelofspo-radiccolorectalcancer,dietary-deliveredgrapeseedextractwasabletoprotectagainstazoxymethane-inducedcolontumorigenesisbydecreasingbothtumordevelopmentandoveralltumorsize(120).MechanisticanalysesrevealedthatgrapeseedextractmodulatedmiRNAexpressionprofiles,aswellasmiRNAprocessingmachinery,andthatthiswasassociatedwithanoverallrepressionincytokineandinflammatorysignaling(120).Importantly,thebioactivecomponentsofgrapeseedextractarealsowelltoleratedinhumans(121).Thisisintriguingbecausenonsteroidalanti-inflammatorydrugshavedemonstratedanticancerproper-ties,butareassociatedwithincreasedgastrointestinalsideeffects(122).Thus,themiRNA-mediatedanti-inflammatorypropertiesofgrapeseedextractinhumansshouldbefurtherinvestigated.Inanotheranimalmodelofcolorectalcancer,HT-29coloncancercellswereinjectedinmice,whichwerethenplacedoneitheracontroloranisoenergeticwalnut-containingdiet.Tumorsofmiceconsumingthewalnut-containingdiethadsignificantlyhigherconcentrationsofω-3(n–3)fattyacids,whichwasassociatedwithsignificantlydecreasedtumorsize(123).Thesefindingsarequiteexcitingbecausethewalnutamountintheanimaldietwasequivalenttoaveryachievable2servings/dforhumans(123).ItisimportanttonotethatthechangesinmiRNAexpressioninducedbychronicwalnutconsumptionswereverymodest,eveninageneticallyhomogeneousstrainofmiceonacontrolleddiet.Thus,measurablediet-inducedchangesinmiRNAexpressionmaybedifficulttoassessinadiversehumanpopulation,althoughtheirphysiologicimpactcouldbequitepowerful.Forexample,ithaspreviouslybeenestablishedthatresis-tantstarchesthatgetmetabolizedintoSCFAsareprotectiveagainstcolorectalcancer,whereashighredmeatintakeisassociatedwithanincreasedrisk.MostoftheseprotectiveeffectsareattributedtothepowerfulHDACinhibitorypropertiesofSCFAs,suchasbutyrate;butSCFAshavethecapacitytoinfluencemiRNAexpressionaswell.Inastudyofhealthyhumanvolunteers,dietarysupplementationwithbutyrylatedhigh-amylosemaizestarchwasabletoprotectagainsttheinductionofoncogenicmiRNAsintherectalmucosaofpeopleeatingadiethighinredmeat(124).1018MontgomeryandSrinivasanDownloaded 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TABLE3ChemopreventiveregulationofmiRNAbybioactivedietarycompounds1BioactivecomponentSourceTargetncRNAAnticancereffectsTypeofcancerModelsystemReferenceAll-transretinoicacidVitaminAmiR-10a,15a/16-1,107,223,Let-7a-3/let7↓Invasiveness↑ApoptosisLeukemia,breastcancerLeukemiapatientsandcelllines,humanbreastbiopsies125,126ApigeninFruitsandvegetablesmiR-138↑Apoptosis↓TumorigenesisNeuroblastomaCelllines,mousexenografts127ButyrateSolublefibermiR-17-92acluster↓Proliferation,↑ApoptosisColoncancerHealthyhumansubjects,celllines124,128,129Canolol,4-vinyl-2,6-dimethoxyphenolCrudecanolaoilmiR-7↓Inflammation,↓ProliferationGastriccancerCelllines,humanprostatectomies130CurcuminTurmericmiR-21,22,15-5,20a,27a,34a/c,101,141,200b,200c,203,205,MEG3↑Drugsensitivity↓Proliferation↓InvasivenessT-celllymphoma,pancreaticcancer,coloncancer,prostatecancer,bladdercancerCelllines,chickenembryometastasisassays,mousexenografts,humanbiopsies131–136Curcumin-difluorinatedCurcuminanalogmiR-21,34,200,210,143,Let-7↑Apoptosis↓AngiogenesisPancreaticcancer,coloncancerCelllines,mouseorthotopicxenografts,humanbiopsies137–140DiallyldisulphideGarlicmiR-34a↓Proliferation↓MetastasisBreastcancerCelllines1411α,25-DihydroxycholecalciferolVitaminDmiR-22,98,181a,181b,627↓Proliferation↓InvasivenessBreastcancer,coloncancer,prostatecancerCelllines,mousexenografts142–1453,3-DiindolylmethaneCruciferousvegetablesmiR-21,31,34a,130a,146b,377↓Proliferation,↑ApoptosisLungcancer,prostatecancerCelllines,humanprostatectomies,mousecarcinogen-inducedlungcancer146,147DocosahexaenoicacidFishoilmiR-15b,16,21,22,107,143,145,191,324-5p↑Apoptosis↓InflammationColoncancer,breastcancer,gliomaCelllines,mousexenografts,ratcarcinogen-inducedcoloncancer148–151EllagicacidPomegranatemiR-27a,126,155,215,224↑Apoptosis↓Proliferation↓InflammationBreastcancer,coloncancerCelllines,ACIrats,ratcarcinogen-inducedcoloncancer,humancolorectalcancerpatients152–156EGCGGreenteamiR-16,34a,145,200c,449c-5p,Let7b↑Apoptosis↓ProliferationColoncancer,lungcancer,melanomaCelllines,mousexenografts,mousecarcinogen-inducedlungcancer157–160FolicacidmiR-21,16a,34a,122,127,200b↓ApoptosisHepatocellularcarcinoma,colorectalcancerMethyl-deficientrats,humanbiopsies,humanpatientswithadenomatouscolonpolyps161–163GenisteinSoymiR-29a,34a,574-3p,1256,HOTAIR↓Proliferation,↓Invasiveness↑ApoptosisProstatecancer,melanomaCelllines,humanbiopsies164–167α-MangostinMangosteenmiR-143↑ApoptosisColoncancerCelllines168PEITCCruciferousvegetablesmiR-194↓InvasivenessProstatecancerCelllines119ω-3(n–3)PUFAsFishoil,walnutsmiR-16,19b,21,26b,27b,93,203,297a↑Apoptosis↓Proliferation↓AngiogenesisColoncancerMousexenografts,mouseandratcarcinogen-inducedcoloncancer123,148,169,170ProanthocyanidinsGrapeseedextractmiR-19a,20a,21,104,148,196a,205,Let-7a↑Apoptosis↓Proliferation↓InflammationColoncancerMousecarcinogen-inducedcoloncancer120ResveratrolStilbenesmiR-17,21,34c,328↑Apoptosis↓Proliferation↓InvasivenessProstatecancer,pancreaticcancer,coloncancer,osteosarcomaCelllines,mousexenografts,humanbiopsies171–175α-TocopherolVitaminEmiR-122,125b↓InflammationNormalratliverVitaminE–deficientrats1761EGCG,(–)-epigallocatechin3-gallate;HOTAIR,HOXtranscriptantisenseRNA;PEITC,phenethylisothiocyanateDietaryepigeneticregulatorsincancer1019Downloaded from https://academic.oup.com/advances/article/10/6/1012/5491277 by guest on 25 May 2023
Importantly,theintakeoftheresistantstarchwithhighredmeatintakealsocorrelatedwithincreasedexpressionofthetumorsuppressorgenephosphataseandtensinhomolog(PTEN),anddecreasedcellproliferationinrectalbiopsiesofhealthypatientscomparedwiththoseconsumingthehighredmeatdietalone(124).ThisstudyhighlightsthepotentialfortheprotectiveandpreventativeeffectsondietarymodulationofmiRNAincancerprevention.Unfortunately,thechemopreventiveeffectsofdietarycompoundsseeninvitroarenotveryfrequentlyrecapitulatedinvivo.Inadouble-blind,randomizedcontrolledclinicaltrialinvestigatingtheinfluenceofpomegranateellagicacidonmiRNAexpressioninthenormalandmalignanttissuesofcolorectalcancerpatients,theresearchersnotedonlymodestchangesinmiRNAexpression(152).Further-more,themajorityoftheobserveddifferencesinmiRNAexpressionbetweennormalandmalignanttissueswerelargelyattributabletothetissueremovalprocess,castingdoubtontheclinicalrelevanceofmiRNAexpressionchanges(152).Thus,althoughmiRNA-mediatedchangesingeneexpressionmayhavesignificantphysiologicimplications,theuseofmiRNAexpressionprofilingmayneverfindwidespreadclinicalutility.Anotherareaofincreasingre-searchinterestwithregardstomiRNAisinvestigatingtheutilityofdietary-derivedmiRNAstoinfluencegeneexpressionandcancerrisk,butresultstodateremaincontroversial(177,178).Part3:necessaryprecautionsfordiet-basedchemopreventivestrategiesAsmentionedabove,poorbioavailabilityofdietary-derivedbioactivecompoundsmaybeaprimaryreasonwehavenotbeenabletorecapitulatethecancerpreventativeresultsofpreclinicalstudies(179).Forexample,ellagicacid(whichisfoundinfoodssuchaswalnuts,berries,andpomegranates)isonlyslightlyabsorbed,andisinsteadextensivelymetab-olizedwithinthegutmicrobiotatourolithins,ofwhichurolithinAexhibitsthemostpromisinganti-inflammatoryandanticarcinogenicproperties(180).However,followingellagicacidingestion,urolithinAproductionisdepen-dentuponthegeneexpression,bodyweight,andeventhegutmicrobialecologyoftheindividual(181,182).Interestingly,individualscanbecategorizedinto3distinctellagitannin-metabolizingphenotypes,or“metabotypes,”andthismetabotypingcanbeusedtoexplaininterindividualvariabilityintheimprovementofcardiovascularriskmarkersinindividualsconsumingpomegranate(183).EllagicacidmetabotypecouldnotbeusedtoexplaininterindividualvariabilityingeneandmiRNAexpressionchangesincol-orectalpatientsfollowingpomegranateextractconsumptionhowever(152,181).Thus,wheninvestigatingthecancerprotectivecapacityofdietarycompounds,itisnecessarytoconsidertheindividualdifferencesinmetabolismandthephysiologicachievabilityofeffectiveconcentrationsoftheirbiologicallyactivemetabolites.Thetranslatabilityofthetissue/cellculturemodelbeingutilizedtounderstand-ingepigeneticmodulationbythedietshouldalsobeconsidered.Moreover,itisworthnotingthatdespitethepromisingre-sultsoflaboratorystudiesandsmall-scaleclinicaltrials,veryfewdietaryinterventionstrategieshavebeenshowntobeeffectivecancer-preventativeagentsinhumantrials.Indeed,manytrialshavebeentoutedasoverwhelmingfailures(184).Intherandomized,double-blinded,placebo-controlledα-tocopherolandβ-caroteneprimarypreventiontrial,20mgβ-carotenesupplementationperdayunexpectedlyincreasedlungcancerincidenceby18%(185).Likewise,intheβ-caroteneandretinolefficacytrial,dailysupplementationwithacombinationof30mgβ-caroteneand25,000IUretinol(vitaminA)increasedtherelativeriskoflungcancerbynearly28%(186).However,thesestudieswereconductedinsmokersorworkersexposedtoasbestos,andthusadiet×environmentaleffectcannotberuledoutasanexplanationofthesenegativeresults.Inasecondaryendpointanalysis,50mgofα-tocopherolacetateperdaywasassociatedwitha45%decreaseinprostatecancerincidence(187).Contrarilyhowever,intheSeleniumandVitaminECancerPreventionTrial,dailysupplementationwith400mgofα-tocopherylacetatesignificantlyincreasedprostatecancerrisk(188).ThelargedifferencesindosesandvitaminEsourcescouldpotentiallyexplaintheseconflictingfindings,butapieceofdatathatisnotablymissingfrombothcohortsisthestartingα-tocopherolstatusofthesubjects,whichcouldalsohavesignificantlyaffectedtheoutcomes.Thefailureofnutrientsupplementationtoeffectivelypre-ventcancerislikelymultifactorial,butinhindsightwenowrecognizethatnutrient-basedpreventionmaynotbeeffectiveinsubjectswithadequatenutritionalstatus.TheLinxianNu-tritionalInterventionTrialfoundthatsupplementationwithacombinationofα-tocopherol(50mg),β-carotene(15mg),andselenium(50μg)protectedagainstcancerincidenceandmortality,butitwasperformedinapopulationwithrecog-nizedlowintakesofmicronutrientsandsignificantnutrientinsufficiencies(189).Similarly,intheNutritionalPreventionofCancerStudyconductedintheeasternUnitedStates,seleniumsupplementationwasfoundtobebeneficial,butonlyinindividualswithlowbaselineconcentrationsofserumselenium(190).Moreover,intheSeleniumandVitaminECancerPreventionTrial,dailysupplementationwith400mgα-tocopherylinpatientswithadequateconcentrationsofplasmaα-tocopherolactuallydecreasedcirculatingconcen-trationsofγ-tocopherolby50%(191).Becauseγ-tocopherolisalsosuspectedtoplayasignificantroleinprostatecancerprevention,thisdecreasehasbeenimplicatedinthesignificantincreaseinprostatecancerriskthatwasobserved(36).Thispointisfurtherunderscoredbyepidemiologicevidencethatsuggeststhatdeficienciesinironandzinc,aswellasfolate,andvitaminsB-12,B-6,andC,canincreasecancerrisk(192).Thus,nutrient-basedchemopreventiveeffortsarelikelybestgearedtowardscorrectingnutritionalinadequacies.1020MontgomeryandSrinivasanDownloaded 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Inadditiontonutritionalstatus,propertimingofdietaryinterventionsiscriticaltosuccessfuldietary-basedchemo-preventiveefforts.FindingsfromtheDutchhungerwinterfamine,andmorerecentworkinvestigatingtheimpactofmaternalobesity,clearlyindicatethatearly-lifeexposuresareintegralriskfactorsforcancerdevelopment(60,61).Moreover,animalstudieshaveclearlyillustratedtheroleofthematernaldietduringpregnancyintheepigeneticmodificationsassociatedwithcancerformation(193–195).Althoughlifelongdiet-basedinterventionsarenotrealistic,evidencesuggeststhatdietarychemopreventiveeffortscanstillbeeffectiveaslongassupplementationbeginsbeforetheestablishmentofprecancerouslesions(36).Forexample,intheLinxianNutritionalInterventionTrial,thecombinationofα-tocopherol/β-carotene/seleniumwasprotectiveagainstesophagealsquamouscellcarcinomainsubjectsaged<55y,butnotinthoseaged>55y(196).Thiswaslikelybecausesomedegreeofdysplasiawasprobablyalreadypresentintheolder,at-riskpopulation(197).Thus,itmaybeimportanttointegratecancer-screeningprocessesintodietarychemopreventiveapproaches.Duetotheinherentchallengesoflifelongdietaryandlifestyleinterventions,itmayalsobenecessarytoonlytargethigh-riskgroupsthatarethemostlikelytobenefitfromsuchbehavioralmodifications.Yetevenifweidentifyatargetgroupthatwouldmostlikelyadhereto,andbenefitfrom,adietarychemopreventionstrategy,thequestionthenbecomeshowwillwetesttheefficacyoftheintervention?Unlikegeneticmarkers,epigeneticbiomarkersareconfoundedbynumerousvari-ablesinadditiontodiet,suchasage,environment,andlifestyle.Thus,toassesstheefficacyofadietaryinterventiononanepigeneticmarkerforcancerpreventionitwouldfirstbenecessarytoidentifyadefinedbiomarkerthatiseitheralwayspresentoralwaysabsentinallnoncancer-ousindividuals,andthatisnotsusceptibletoenviron-mentalinfluences.Todate,asinglesuchbiomarkerhasnotbeenidentified,buttheutilityofassessingepigeneticmarksasacomponentofclinicalscreeningshasbeenestablished.MeasurementofSeptin9methylationisnowapartofanFDA-approvedscreeningpanelforthedetectionofcoloncancer(198).Likewise,lackofmethylationwithinthepromoteroftheDNArepairenzymeO6-methylguanine-DNAmethyltransferasecanbeusedtopredicttreatmentresponseinadultglioblastomapatients(199).Itisalsoworthmentioningthatinadditiontonext-generationsequencingtoinvestigatencRNAabundance,itisnowpossibletoperformrapidunbiasedanalysisofthetotalDNAmethylome,aswellaslarge-scaleprofilingofhistonemodifications(200).Thereis,then,considerablehopeforidentifyingchemopreventiveepigeneticmarkers,butitwillfirstbenecessarytodistinguisha“healthy”epigeneticpatternbeforetheutilityofepigenomicprofilingcanberealized.ConclusionsGiventhelonglatencyofmostcancers,andthephysio-logicfactorsthatareknowntobecriticalduringcancerdevelopment,early-stagelifestyleinterventionswilllikelybekeytosuccessfuldietary-basedchemoprevention.Thispointisunderscoredbyevidenceindicatingthatdietary-basedchemopreventiveeffortsaremostefficaciousinindividualsinwhomnoearlysignsofcancerhavebeendetected(36,196,197).Inherentdifficultiesassociatedwiththisstrategy,however,aredeterminingtheappropriatetreatmentduration,andassessingtreatmentefficacyinasymptomaticindividuals.However,recentstudiesdescribingtheutilityofan“epigeneticclock”thatcanbeassessedtopredictdiseaseriskbasedonepigeneticagemayprovideguidanceforidentifyingoptimaltimingfordietary-basedepigeneticinterventionstrategies(201,202).Furthermore,becausepatientcompliancecanbeproblematicinlong-termdietinterventiontrials,itmaybenecessarytotargetthosehigh-riskgroupsthataremostlikelytobenefitfromsuchabehavioralmodification.Thus,regularcancerscreenings,andpatienteducationshouldalsobeintegratedintothedesignofchemopreventivestudies.Itmayalsobethattherearestagesoflife,suchasearlydevelopment,inwhichcertainregionsofthegenomearemorevulnerabletoepigeneticalterations.Forexample,inuteroexposuretobothdietaryrestrictionandexcesscanresultinlastingchangestoDNAmethylation,andtheseal-terationsareassociatedwithincreaseddiseasesusceptibility(60,203).Andalthoughconceptually,epigeneticmodifica-tionsarereversible,evidencenowindicatesthatprolongedexposuretoepigeneticaberrationsmayeventuallyleadtoirreversiblealterations(204).Wemustthenunderstandboththefunctionalconsequencesofepigeneticmarksandtheassociatedtemporalrelationsbetweenthesemarksbeforewecanprescribeeffectivediet-basedinterventions.Theuseofnewtechnologies,suchCRISPR,thatallowfortherecruit-mentofspecificepigeneticwritersandtargetedepigeneticmodificationswilllikelyproveinvaluableforunderstandingtheepigeneticcontrolmechanismsthatcontributetocanceretiology.Wheninvestigatingthechemopreventiveefficacyofdi-etaryagentsitisalsoimportanttoconsiderthatbecauseofextensivemetabolicprocesses,dietaryintakedoesnotnecessarilyreflecttissueortumorexposuretobiologicallyactivecompounds.Achemopreventivedietaryagentcanonlybeeffectiveifsufficientconcentrationsofthebio-logicallyactivecomponentsactuallyreachtargetorgans.Accordingly,measurestoenhancebioavailabilityofthebioactivecomponent,suchasoptimizingthedosingregimen,incorporatingitintoadrug-deliverysystem,orsynthesizingmorestablebioactiveanalogs,shouldbetaken.Inthisregard,itmayalsobenecessarytoassessthemetabolicphenotypeoftheindividualaswell.Particularlyforthosebioactivecomponentswhichareextensivelymetabolizedbythegutmicrobiota,asmicrobialmetabolismcanhaveasignificantimpactonhostepigeneticprogramming(205)andcarcinogenesis[reviewedin(206)].Nutritionalstatuscanalsoinfluencethechemopreven-tiveefficacyofdietarycompounds.Currently,thereisnoevidencethatindividualnutrientscanorwillbeabletobeusedaspharmaceuticalchemopreventiveagents,exceptDietaryepigeneticregulatorsincancer1021Downloaded 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forinindividualsinwhomthatnutrientislacking.Indeed,preventingdeficienciesinnutrients,suchasiron,zinc,folate,andvitaminsB-6,B-12,andC,hasbeensuggestedtoplayanimportantroleincancerprevention(192).ThechemopreventiveeffectsofadequatevitaminandmineralstatusesarelargelyattributedtothepreventionofDNAdamage,butrecentlyirondeprivationwasalsolinkedtoaberrantchangesinhistoneacetylationandmethylation(207).NewevidencealsosuggeststhatvitaminCmayhelpregulatehematopoieticstemcellfunctionandprotectagainstleukemiaprogressionviaDNAdemethylation(208,209).VitaminChasalsobeenshowntoaugmenttheeffectivenessoftheclinicallyusedDNMTinhibitor,5-azacytidine,whichcouldhavesignificanttherapeuticimplications(210,211).Thesefindingsuggestthatepigeneticmodificationsmaybeyetanothermeansbywhichmicronutrientavailabilityaffectscancerdevelopment,andwarrantcontinuedinvestigation.However,becauseindividualdietscontainamixtureofhealthyandlesshealthfulcon-stituentsthatcancontributetotheoverallchemopreventiveefficacyofabioactivecompound,wearelikelybetterofffocusingontheoveralldietarypatternratherthanonaspecificdietaryagent.Indeed,synergisticeffectsofdietarybioactivecompoundshavebeennoted(80,212–214),andevenpharmacologicepigenetictherapiesareseldomusedassingleagents,butratherincombinationwithotherchemotherapeutics(26).Theaugmentedtherapeuticefficacyofcombinatorialepigenetictreatmentsfurtherhighlightstheimportanceofconsideringthechemopreventiveactionsofagivendietarycompoundwithinthefulldiet,andinthecontextofanentirelifestyle.Undoubtedly,thepromotionofahealthylifestylethatincludesregularphysicalactivity,preventionofoverweightandobesity,andabstainingfromsmokingwouldundoubtedlyimprovethechemopreventiveefficacyofanysinglebioactivedietarycomponent.AcknowledgmentsTheauthors’responsibilitieswereasfollows—MM:concep-tualizedthereview,conductedtheliteraturesearch,andwrotethemanuscript;AS:developedandformattedthetables,andcriticallyreviewedthemanuscript;andbothauthors:readandapprovedthefinalmanuscript.References1.KeyTJ,SchatzkinA,WillettWC,AllenNE,SpencerEA,TravisRC.Diet,nutritionandthepreventionofcancer.PublicHealthNutr2004;7:187–200.2.WHO.Obesityandoverweight.WHO;2017.3.SpornMB,DunlopNM,NewtonDL,SmithJM.PreventionofchemicalcarcinogenesisbyvitaminAanditssyntheticanalogs(retinoids).FedProc1976;35:1332–8.4.JinB,LiY,RobertsonKD.DNAmethylation:superiororsubordinateintheepigenetichierarchy?GenesCancer2011;2:607–17.5.RobertsonKD.DNAmethylationandchromatin—unravelingthetangledweb.Oncogene2002;21:5361–79.6.TammenSA,FrisoS,ChoiSW.Epigenetics:thelinkbetweennatureandnurture.MolAspectsMed2013;34:753–64.7.ProbstAV,DunleavyE,AlmouzniG.Epigeneticinheritanceduringthecellcycle.NatRevMolCellBiol2009;10:192–206.8.WolffGL,KodellRL,MooreSR,CooneyCA.MaternalepigeneticsandmethylsupplementsaffectagoutigeneexpressioninAvy/amice.FASEBJ1998;12:949–57.9.SimmonsD.Epigeneticinfluenceanddisease.NatureEduc2008;1(1):6.10.BoldenJE,PeartMJ,JohnstoneRW.Anticanceractivitiesofhistonedeacetylaseinhibitors.NatRevDrugDiscov2006;5:769–84.11.BannisterAJ,KouzaridesT.Regulationofchromatinbyhistonemodifications.CellRes2011;21:381–95.12.CaoJ,YanQ.Histoneubiquitinationanddeubiquitinationintranscription,DNAdamageresponse,andcancer.FrontOncol2012;2:26.13.MattickJS,MakuninIV.Non-codingRNA.HumMolGenet2006;15(Specno1):R17–29.14.ChoiSW,FrisoS.Epigenetics:anewbridgebetweennutritionandhealth.AdvNutr2010;1:8–16.15.ChuangKH,Whitney-MillerCL,ChuCY,ZhouZ,DokusMK,SchmitS,BarryCT.MicroRNA-494isamasterepigeneticregulatorofmultipleinvasion-suppressormicroRNAsbytargetingteneleventranslocation1ininvasivehumanhepatocellularcarcinomatumors.Hepatology2015;62:466–80.16.MalumbresM.miRNAsandcancer:anepigeneticsview.MolAspectsMed2013;34:863–74.17.YuanJH,YangF,ChenBF,LuZ,HuoXS,ZhouWP,WangF,SunSH.Thehistonedeacetylase4/SP1/microrna-200aregulatorynetworkcontributestoaberranthistoneacetylationinhepatocellularcarcinoma.Hepatology2011;54:2025–35.18.MacfarlaneLA,MurphyPR.MicroRNA:biogenesis,functionandroleincancer.CurrGenomics2010;11:537–61.19.LiuQ,HuangJ,ZhouN,ZhangZ,ZhangA,LuZ,WuF,MoYY.LncRNAloc285194isap53-regulatedtumorsuppressor.NucleicAcidsRes2013;41:4976–87.20.WangKC,ChangHY.MolecularmechanismsoflongnoncodingRNAs.MolCell2011;43:904–14.21.EstellerM.Non-codingRNAsinhumandisease.NatRevGenet2011;12:861–74.22.CalinGA,CroceCM.MicroRNAsignaturesinhumancancers.NatRevCancer2006;6:857–66.23.GutschnerT,DiederichsS.Thehallmarksofcancer:alongnon-codingRNApointofview.RNABiol2012;9:703–19.24.ZhangB,PanX,CobbGP,AndersonTA.MicroRNAsasoncogenesandtumorsuppressors.DevBiol2007;302:1–12.25.CoppedeF,LopomoA,SpisniR,MiglioreL.Geneticandepigeneticbiomarkersfordiagnosis,prognosisandtreatmentofcolorectalcancer.WorldJGastroenterol2014;20:943–56.26.JonesPA,IssaJP,BaylinS.Targetingthecancerepigenomefortherapy.NatRevGenet2016;17:630–41.27.ShahN,LinB,SibenallerZ,RykenT,LeeH,YoonJG,RostadS,FoltzG.ComprehensiveanalysisofMGMTpromotermethylation:correlationwithMGMTexpressionandclinicalresponseinGBM.PLoSOne2011;6:e16146.28.FuentesF,Paredes-GonzalezX,KongAT.Dietaryglucosi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