REVIEWARTICLEOPENTheroleofubiquitinationintumorigenesisandtargeteddrugdiscoveryLuDeng1,TongMeng2,LeiChen3,WenyiWei4andPingWang5Ubiquitination,animportanttypeofproteinposttranslationalmodification(PTM),playsacrucialroleincontrollingsubstratedegradationandsubsequentlymediatesthe“quantity”and“quality”ofvariousproteins,servingtoensurecellhomeostasisandguaranteelifeactivities.Theregulationofubiquitinationismultifacetedandworksnotonlyatthetranscriptionalandposttranslationallevels(phosphorylation,acetylation,methylation,etc.)butalsoattheproteinlevel(activatorsorrepressors).Whenregulatorymechanismsareaberrant,thealteredbiologicalprocessesmaysubsequentlyinduceserioushumandiseases,especiallyvarioustypesofcancer.Intumorigenesis,thealteredbiologicalprocessesinvolvetumormetabolism,theimmunologicaltumormicroenvironment(TME),cancerstemcell(CSC)stemnessandsoon.Withregardtotumormetabolism,theubiquitinationofsomekeyproteinssuchasRagA,mTOR,PTEN,AKT,c-MycandP53significantlyregulatestheactivityofthemTORC1,AMPKandPTEN-AKTsignalingpathways.Inaddition,ubiquitinationintheTLR,RLRandSTING-dependentsignalingpathwaysalsomodulatestheTME.Moreover,theubiquitinationofcorestemcellregulatortriplets(Nanog,Oct4andSox2)andmembersoftheWntandHippo-YAPsignalingpathwaysparticipatesinthemaintenanceofCSCstemness.Basedonthealteredcomponents,includingtheproteasome,E3ligases,E1,E2anddeubiquitinases(DUBs),manymoleculartargeteddrugshavebeendevelopedtocombatcancer.Amongthem,smallmoleculeinhibitorstargetingtheproteasome,suchasbortezomib,carfilzomib,oprozomibandixazomib,haveachievedtangiblesuccess.Inaddition,MLN7243andMLN4924(targetingtheE1enzyme),LeucettamolAandCC0651(targetingtheE2enzyme),nutlinandMI‐219(targetingtheE3enzyme),andcompoundsG5andF6(targetingDUBactivity)havealsoshownpotentialinpreclinicalcancertreatment.Inthisreview,wesummarizethelatestprogressinunderstandingthesubstratesforubiquitinationandtheirspecialfunctionsintumormetabolismregulation,TMEmodulationandCSCstemnessmaintenance.Moreover,potentia...
