| Triple negative breast cancer(TNBC,ER-/PR-/HER2-)is an aggressive clinical phenotype characterized by high degree of malignancy,poor prognosis,poor response to endocrine therapy and targeted therapy for HER2.Up to now,cytotoxic chemotherapy remains to be the mainstay of treatment of triple negative breast cancer Hence,there is an urgent need for precise targeted therapy in TNBC.Ubiquitination played an important role in a wide variety of cellular processes,such as,cell cycle progression,apoptosis,receptor downregulation,and gene transcription.In recent years,substantial achievements had been made on revealing the molecular basis of ubiquitination in tumor development.Numerous components of the ubiquitin system associated with cancer were exposed and explored to be targets for therapeutic strategies against tumour.In this study,the rapid developped CRISPR/Cas9 technology and genetic screening were combined to explore essential genes of TNBC among the ubiquitin system.The present investigation was purposed:one to deepen the understanding of the roles that ubiquitination played in the development of TNBC and secondly to find more new targets for TNBC.We had successfully identified several essential genes for TNBC,such as deubiquitinase USP28,and the apoptosis-related gene BIRC6,etc.Then USP28 was focused for further cellular and biochemical studies,in order to clarify its potential role in TNBC.Immunohistochemical analysis showed that USP28 was highly expressed in TNBC.Lentivirus-mediated USP28 knockdown could significantly inhibit the growth of TNBC.Importantly,molecular mechanism studies reveal that USP28 regulated the ubiquitination and stability of DNA helicase RecQL5.Moreover,RecQL5 depletion could also suppress the proliferative ability and the genomic stability of TNBC.In sum,our findings suggest that deubiquitinase USP28 and DNA helicase RecQL5 were essential for the growth of triple-negative breast cancer cells and expected to be potential therapeutic targets for TNBC. |
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