BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is ...BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.展开更多
Inflammatory bowel disease(IBD)is a chronic inflammatory disorder of the gastrointestinal tract,which increases the incidence of colorectal cancer(CRC).In the pathophysiology of IBD,ubiquitination/deubiquitination pla...Inflammatory bowel disease(IBD)is a chronic inflammatory disorder of the gastrointestinal tract,which increases the incidence of colorectal cancer(CRC).In the pathophysiology of IBD,ubiquitination/deubiquitination plays a critical regulatory function.Josephin domain containing 2(JOSD2),a deubiquitinating enzyme,controls cell proliferation and carcinogenesis.However,its role in IBD remains unknown.Colitis mice model developed by dextran sodium sulfate(DSS)or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages.JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation.DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation.Mechanistically,JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2(IMPDH2)and preferentially cleaves K63-linked polyubiquitin chains at the K134 site,suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B(NF-κB)and inflammation in macrophages.It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane(AOM)/DSS-induced CRC,and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice.These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2,suggesting that targeting JOSD2 is a potential strategy for treating IBD.展开更多
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
基金Supported by Tianjin Key Medical Discipline(Specialty)Construction Project,No.TJYXZDXK-009ATianjin Medical University Cancer Hospital National Natural Science Foundation Cultivation Program,No.220108+3 种基金National Natural Science Foundation of China,No.82373134Science and Technology Development Fund of Tianjin Education Commission for Higher Education,No.2022KJ228Chinese Anti-Cancer Association-Heng Rui Anti-angiogenesis Targeted Tumor Research Fund,No.2021001045and Scientific Research Translational Foundation of Wenzhou Safety(Emergency)Institute of Tianjin University,No.TJUWYY2022025.
文摘BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.
基金supported by the National Natural Science Foundation of China(82300589 to Xin Liu,82004042 to Mincong Huang,and 82370244 to Yi Wang)the Zhejiang Provincial Key Scientific Project(2021C03041 to Guang Liang,China).
文摘Inflammatory bowel disease(IBD)is a chronic inflammatory disorder of the gastrointestinal tract,which increases the incidence of colorectal cancer(CRC).In the pathophysiology of IBD,ubiquitination/deubiquitination plays a critical regulatory function.Josephin domain containing 2(JOSD2),a deubiquitinating enzyme,controls cell proliferation and carcinogenesis.However,its role in IBD remains unknown.Colitis mice model developed by dextran sodium sulfate(DSS)or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages.JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation.DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation.Mechanistically,JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2(IMPDH2)and preferentially cleaves K63-linked polyubiquitin chains at the K134 site,suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B(NF-κB)and inflammation in macrophages.It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane(AOM)/DSS-induced CRC,and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice.These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2,suggesting that targeting JOSD2 is a potential strategy for treating IBD.
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.
