Triple-negative breast cancer(TNBC)is an aggressive disease characterized by high metastatic potential and limited treatment options.Protein kinase C-eta(PKCη),an antiapoptotic kinase of the novel PKC subfamily,is as...Triple-negative breast cancer(TNBC)is an aggressive disease characterized by high metastatic potential and limited treatment options.Protein kinase C-eta(PKCη),an antiapoptotic kinase of the novel PKC subfamily,is associated with poor prognosis in breast cancer patients.Analysis of TNBC tumors revealed that PRKCH(PKCη)expression is linked to an epithelial‒mesenchymal transition(EMT)signature,which is indicative of a metastatic phenotype.Using genetic ablation studies,we showed that PKCηpromotes metastasis by enhancing EMT and stemness.Notably,compared with those in PKCη-intact tumors,orthotopic xenografts of PKCη-knockout cells in NSG mice resulted in reduced tumor growth and metastasis.Mechanistically,PKCηfunctions as a negative regulator of the Hippo pathway by activating YAP.PKCηphosphorylates YAP at Ser128,leading to its stabilization and nuclear translocation,which promotes metastasis.We also demonstrated that PKCηnegatively regulates AKT,thereby further sustaining the downregulation of the Hippo pathway.Finally,we show that an evolutionarily conserved peptide encoded by an upstream open reading frame(uORF)preceding the PKCηcoding sequence functions as a PKCηdegrader,activating the Hippo pathway and promoting YAP degradation.Together,our findings reveal a PKCη-driven signaling axis that regulates the Hippo-YAP pathway in TNBC metastasis,highlighting the potential therapeutic vulnerability of this aggressive disease.展开更多
Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therape...Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently needed.Natural products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer activities.Recently,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.展开更多
基金funded by the Israel Science Foundation:ISF 3280/24 to Etta Livneh,Ministry of Science,Technology and Space#4981 to Etta LivnehISF,302/21 to Moshe Elkabets+2 种基金ISF,2802/22 to Ofir Cohen.The United States-Israel Binational Science Foundation:BSF,#2021055 to Moshe Elkabets,#2023129 to Ofir Cohen.Ministry of Innovation,Science&Technology:MOST,#5912 to Moshe Elkabets and Ofir CohenAcceleration was granted by the Israel Cancer Research Foundation:ICRF,#1060612 to Moshe Elkabets and ICRF#81233611 to Ofir CohenVijayasteltar B Liju was awarded a Kreitman postdoctoral fellowship from Ben-Gurion University of the Negev,Beersheva,Israel.
文摘Triple-negative breast cancer(TNBC)is an aggressive disease characterized by high metastatic potential and limited treatment options.Protein kinase C-eta(PKCη),an antiapoptotic kinase of the novel PKC subfamily,is associated with poor prognosis in breast cancer patients.Analysis of TNBC tumors revealed that PRKCH(PKCη)expression is linked to an epithelial‒mesenchymal transition(EMT)signature,which is indicative of a metastatic phenotype.Using genetic ablation studies,we showed that PKCηpromotes metastasis by enhancing EMT and stemness.Notably,compared with those in PKCη-intact tumors,orthotopic xenografts of PKCη-knockout cells in NSG mice resulted in reduced tumor growth and metastasis.Mechanistically,PKCηfunctions as a negative regulator of the Hippo pathway by activating YAP.PKCηphosphorylates YAP at Ser128,leading to its stabilization and nuclear translocation,which promotes metastasis.We also demonstrated that PKCηnegatively regulates AKT,thereby further sustaining the downregulation of the Hippo pathway.Finally,we show that an evolutionarily conserved peptide encoded by an upstream open reading frame(uORF)preceding the PKCηcoding sequence functions as a PKCηdegrader,activating the Hippo pathway and promoting YAP degradation.Together,our findings reveal a PKCη-driven signaling axis that regulates the Hippo-YAP pathway in TNBC metastasis,highlighting the potential therapeutic vulnerability of this aggressive disease.
基金the National Natural Science Foundation of China(82073890,81673464,and 82061148017,to DK,22137006 and 82104054,to HW L)Fellowship of China Postdoctoral Science Foundation(2021M702464 to XP)Postgraduate Innovation Fund of 13th Five-Year comprehensive investment of Tianjin Medical University(YJSCX201806 to XP).SF295 cell line was kindly provided by the National Cancer Institute,National Institutes of Health,USA.We thank Dr.Xi Chen from Tianjin Key Laboratory of Ophthalmology and Visual Science,Tianjin Eye Institute,Tianjin Eye Hospital for assistance in spectrometry proteomics data analysis.
文摘Dear Editor,Glioblastoma(GBM)is one of the most fatal brain tumors.Current first-line post-surgery regimens for GBM including radiotherapy and temozolomide(TMZ)chemotherapy show very limited efficacy.1,2 Novel therapeutic approaches for GBM patients are urgently needed.Natural products are important sources for drug discovery,especially in the field of cancer treatment.3 We previously isolated stellettin B(STELB)(Fig.1a)from marine sponge(Jaspis stellifera)and reported the remarkable and specific anticancer activities.Recently,a series of stellettins has been totally synthesized and the core chemical structure has been indicated.4 However,the specific mechanism and its role in regulating tumor biology remain largely unknown.
