OPENORIGINALARTICLEDBC2/RhoBTB2functionsasatumorsuppressorproteinviaMusashi-2ubiquitinationinbreastcancerYMChoi1,2,KBKim2,JHLee3,YKChun4,ISAn2,SAn1andSBae1Thegeneencoding‘deletedinbreastcancer2’(DBC2),alsoreferredtoasRHOBTB2(Rho-relatedBTBdomain-containingprotein2),isclassifiedasatumorsuppressorgene.DBC2isasubstrate-specificadaptorproteinforanovelclassofCullin-3(CUL3)-basedE3ubiquitinligases;however,itisunclearifthesubstrateadaptorfunctionofDBC2isrequiredforitstumorsuppressoractivity.Furthermore,thekeysubstratesofDBC2-mediatedubiquitinationhaveyettobeidentified.Inthepresentstudy,weestablishedagenome-widehumancDNAlibrary-basedinvitroubiquitinationtargetscreeningassayandidentifiedMusashi-2(MSI2)asanovelubiquitinationtargetproteinofDBC2.MSI2directlyinteractedwithDBC2,andthisinteractionpromotedMSI2polyubiquitinationandproteasomaldegradationinbreastcancercells.OverexpressionandknockdownexperimentsdemonstratedthatDBC2suppressedMSI2-associatedoncogenicfunctionsandinducedapoptosis.ImmunohistochemistryanalysisofabreastcancertissuemicroarrayrevealedthatDBC2andMSI2proteinlevelsareinverselycorrelatedinbothnormalbreasttissuesandbreastcancertissues.Takentogether,thesefindingsprovideevidencethatDBC2suppressestumorigenesisinbreastcancerbyubiquitinatingMSI2.Oncogeneadvanceonlinepublication,12December2016;doi:10.1038/onc.2016.441INTRODUCTIONUbiquitin-mediatedpost-translationalmodificationsareessentialfornearlyallbiologicalprocesses,includingcellgrowth,differ-entiationandapoptosis.1Dysregulationofthisphenomenonleadstoirreversiblechangesinproteinstabilityandcandirectlyorindirectlypromoteavarietyofpathologicalconditions,includingcancer.1TheprocessofubiquitinationinvolvesmultiplestepsmediatedbyE1ubiquitin-activatingenzymes,E2ubiquitin-conjugatingenzymesandsubstrate-specificE3ubiquitinligases.2ThemostpredominantclassofE3ligasesisthefamilyofreallyinterestingnewgene(RING)-fingerdomain-containingproteins.Theseproteinsaresubdividedintotwogroups:themonomericRING-typeE3ligasesandthemultime...
