Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are report...Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are reported to be common in CCA patients.However,the underpinning mechanism remains poorly understood.Deubiquitinase(DUB)is regarded as a main orchestrator in maintaining protein homeostasis.Here,we identified Josephin domain-containing protein 2(JOSD2)as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner.The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo.Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples.Collectively,this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression,which may provide a potential intervention target for YAP/TAZ-related CCA patients.展开更多
While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiat...While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.展开更多
To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins...To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins1.Recently,several strategies have been investigated to address TPD,including targeting E2,E3 for POI degradation2,or employing DUBs to stabilize POI3.Among them,proteolysis targeting chimeras(PROTACs)have emerged as the predominant approach in both preclinical and clinical investigations by connecting an E3 recruiting ligand to a POI ligand4.Proteasome,the primary protease responsible for proteolysis in eukaryotes,is a more central and widely present component in the UPS,consisting mainly of the 19S and 20S subcomplexes5.展开更多
基金supported by the Key Program of the Natural Science Foundation of China(No.81830107)the Natural Science Foundation for Distinguished Young Scholar of China(No.81625024)+1 种基金the Natural Science Foundation of China(No.81773753,No.81973349)the Zhejiang Provincial Natural Science Foundation(No.LR19H310002 and No.LR21H300003,China)。
文摘Cholangiocarcinoma(CCA)has emerged as an intractable cancer with scanty therapeutic regimens.The aberrant activation of Yes-associated protein(YAP)and transcriptional co-activator with PDZ-binding motif(TAZ)are reported to be common in CCA patients.However,the underpinning mechanism remains poorly understood.Deubiquitinase(DUB)is regarded as a main orchestrator in maintaining protein homeostasis.Here,we identified Josephin domain-containing protein 2(JOSD2)as an essential DUB of YAP/TAZ that sustained the protein level through cleavage of polyubiquitin chains in a deubiquitinase activity-dependent manner.The depletion of JOSD2 promoted YAP/TAZ proteasomal degradation and significantly impeded CCA proliferation in vitro and in vivo.Further analysis has highlighted the positive correlation between JOSD2 and YAP abundance in CCA patient samples.Collectively,this study uncovers the regulatory effects of JOSD2 on YAP/TAZ protein stabilities and profiles its contribution in CCA malignant progression,which may provide a potential intervention target for YAP/TAZ-related CCA patients.
基金supported by the National Natural Science Foundation of China(No.U20A20137)the Zhejiang Provincial Natural Science Foundation of China(No.LD21H310001)the Fundamental Research Funds for the Central Universities(No.2021XZZX037,China)。
文摘While neuroblastoma accounts for 15%of childhood tumor-related deaths,treatments against neuroblastoma remain scarce and mainly consist of cytotoxic chemotherapeutic drugs.Currently,maintenance therapy of differentiation induction is the standard of care for neuroblastoma patients in clinical,especially high-risk patients.However,differentiation therapy is not used as a first-line treatment for neuroblastoma due to low efficacy,unclear mechanism,and few drug options.Through compound library screening,we accidently found the potential differentiation-inducing effect of AKT inhibitor Hu7691.The protein kinase B(AKT)pathway is an important signaling pathway for regulating tumorigenesis and neural differentiation,yet the relation between the AKT pathway and neuroblastoma differentiation remains unclear.Here,we reveal the anti-proliferation and neurogenesis effect of Hu7691 on multiple neuroblastoma cell lines.Further evidence including neurites outgrowth,cell cycle arrest,and differentiation mRNA marker clarified the differentiation-inducing effect of Hu7691.Meanwhile,with the introduction of other AKT inhibitors,it is now clear that multiple AKT inhibitors can induce neuroblastoma differentiation.Furthermore,silencing AKT was found to have the effect of inducing neuroblastoma differentiation.Finally,confirmation of the therapeutic effects of Hu7691 is dependent on inducing differentiation in vivo,suggesting that Hu7691 is a potential molecule against neuroblastoma.Through this study,we not only define the key role of AKT in the progression of neuroblastoma differentiation but also provide potential drugs and key targets for the application of differentiation therapies for neuroblastoma clinically.
基金supported by Guangdong High-Level New R&D Institute(2023000003 and 2019B090904008,China)Guangdong High-level Innovative Research Institute(2021B0909050003,China)+2 种基金National Natural Science Foundation of China(82121005,81803432,and 82273951,China)Zhejiang Provincial Natural Science Foundation of China(LY24H300003,China)Scientific Research Foundation of Zhejiang University City College(No.X-202202,China).
文摘To the Editor:Targeted protein degradation(TPD)has emerged as a powerful therapeutic strategy for the treatment of various diseases,including cancer,that are associated with aberrant high levels of pathogenic proteins1.Recently,several strategies have been investigated to address TPD,including targeting E2,E3 for POI degradation2,or employing DUBs to stabilize POI3.Among them,proteolysis targeting chimeras(PROTACs)have emerged as the predominant approach in both preclinical and clinical investigations by connecting an E3 recruiting ligand to a POI ligand4.Proteasome,the primary protease responsible for proteolysis in eukaryotes,is a more central and widely present component in the UPS,consisting mainly of the 19S and 20S subcomplexes5.
