Objective UBR5,recently identified as a potential target for cancer therapeutics,is overexpressed in multiple malignant tumors.In addition,it is closely associated with the growth,prognosis,metastasis,and treatment re...Objective UBR5,recently identified as a potential target for cancer therapeutics,is overexpressed in multiple malignant tumors.In addition,it is closely associated with the growth,prognosis,metastasis,and treatment response of multiple types of cancer.Although emerging evidence supports the relationship between UBR5 and cancer,there are limited cancer analyses available.Methods In this study,online databases(TIMER2,GEPIA2,UALCAN,c-BioPortal,STRING)were employed to comprehensively explore expression levels and prognostic values of the UBR5 gene in cancer,using bioinformatic methods.Results We found that various characteristics of the UBR5 gene such as gene expression,survival value,genetic mutation,protein phosphorylation,immune infiltration,and pathway activities in the normal tissue were remarkably different from those in the primary tumor.Furthermore,“protein processing in spliceosome”and“ubiquitin mediated proteolysis”have provided evidence for their potential involvement in the development of cancer.Conclusion Our findings may provide insights for the selection of novel immunotherapeutic targets and prognostic biomarkers for cancer.展开更多
Metastasis accounts for the major cause of colorectal cancer(CRC)related mortality due to the lack of effective treatments.In this study,we integrated the single-cell RNA-seq(sc RNA-seq)and bulk RNA-seq data and ident...Metastasis accounts for the major cause of colorectal cancer(CRC)related mortality due to the lack of effective treatments.In this study,we integrated the single-cell RNA-seq(sc RNA-seq)and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog(SacSaccharomyces cerevisiae)/PC4(positive cofactor 4)associated with CRC metastasis.Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC.In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells.SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis.Mechanistically,SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells.Subsequently,the increased UBR5mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1,thus to activate the NF-κB signaling.Overall,our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling,providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.展开更多
基金Supported by grants from the Guangxi Natural Science Foundation(No.2019GXNSFBA245032)the Guangxi Science and Technology Plan Project(No.Gui Ke AD20238021)+2 种基金the open funds of the Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation(No.203030302008,203030302018 and 2020KF010)Guilin Science Research and Technology Development Project(No.20190218-5-5)the Basic Ability Enhancement Program for Young and Middle-aged Teachers of Guangxi(No.2021KY0496).
文摘Objective UBR5,recently identified as a potential target for cancer therapeutics,is overexpressed in multiple malignant tumors.In addition,it is closely associated with the growth,prognosis,metastasis,and treatment response of multiple types of cancer.Although emerging evidence supports the relationship between UBR5 and cancer,there are limited cancer analyses available.Methods In this study,online databases(TIMER2,GEPIA2,UALCAN,c-BioPortal,STRING)were employed to comprehensively explore expression levels and prognostic values of the UBR5 gene in cancer,using bioinformatic methods.Results We found that various characteristics of the UBR5 gene such as gene expression,survival value,genetic mutation,protein phosphorylation,immune infiltration,and pathway activities in the normal tissue were remarkably different from those in the primary tumor.Furthermore,“protein processing in spliceosome”and“ubiquitin mediated proteolysis”have provided evidence for their potential involvement in the development of cancer.Conclusion Our findings may provide insights for the selection of novel immunotherapeutic targets and prognostic biomarkers for cancer.
基金supported by the National Natural Science Foundation of China(82073229,82072623)。
文摘Metastasis accounts for the major cause of colorectal cancer(CRC)related mortality due to the lack of effective treatments.In this study,we integrated the single-cell RNA-seq(sc RNA-seq)and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog(SacSaccharomyces cerevisiae)/PC4(positive cofactor 4)associated with CRC metastasis.Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC.In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells.SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis.Mechanistically,SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells.Subsequently,the increased UBR5mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1,thus to activate the NF-κB signaling.Overall,our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling,providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.
