Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and th...Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and the mechanisms that support abnormal AhR expression in CSCs remain elusive.Here,we identified ubiquitin carboxyl terminal hydrolase L3(UCHL3),a DUB enzyme in the UCH protease family,as a bona fide deubiquitylase of the AhR in NSCLC.UCHL3 was shown to interact with,deubiquitylate,and stabilize AhR in a manner dependent on its deubiquitylation activity.Moreover,we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells.UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the“stemness”genes ATP-binding cassette subfamily G member 2(ABCG2),KLF4,and c-Myc.Depletion of UCHL3 markedly downregulated the“stemness”genes ABCG2,KLF4,and c-Myc,leading to the loss of selfrenewal and tumorigenesis in NSCLCs.Furthermore,the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties.Additionally,UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma.In general,our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.展开更多
基金The National Natural Science Foundation of China(81672991 and 81874139[S.L.],81672787[Y.T.],81672308[X.W.])the National Basic Research Program of China(2015CB553903[Y.T.])supported this study.
文摘Cancer stem cells(CSCs)exhibit highly aggressive and metastatic features and resistance to chemotherapy and radiotherapy.Aryl hydrocarbon receptor(AhR)expression varies among non-small cell lung cancers(NSCLCs),and the mechanisms that support abnormal AhR expression in CSCs remain elusive.Here,we identified ubiquitin carboxyl terminal hydrolase L3(UCHL3),a DUB enzyme in the UCH protease family,as a bona fide deubiquitylase of the AhR in NSCLC.UCHL3 was shown to interact with,deubiquitylate,and stabilize AhR in a manner dependent on its deubiquitylation activity.Moreover,we showed that UCHL3 promotes the stem-like characteristics and potent tumorigenic capacity of NSCLC cells.UCHL3 increased AhR stability and the binding of AhR to the promoter regions of the“stemness”genes ATP-binding cassette subfamily G member 2(ABCG2),KLF4,and c-Myc.Depletion of UCHL3 markedly downregulated the“stemness”genes ABCG2,KLF4,and c-Myc,leading to the loss of selfrenewal and tumorigenesis in NSCLCs.Furthermore,the UCHL3 inhibitor TCID induced AhR degradation and exhibited significantly attenuated efficacy in NSCLC cells with stem cell-like properties.Additionally,UCHL3 was shown to indicate poor prognosis in patients with lung adenocarcinoma.In general,our results reveal that the UCHL3 deubiquitylase is pivotal for AhR protein stability and a potential target for NSCLC-targeted therapy.
