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PKC-eta promotes breast cancer metastasis by regulating the Hippo-YAP signaling pathway 认领 引用
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作者 Vijayasteltar B.Liju Kamran Waidha +12 位作者 Amitha Muraleedharan Divya Ram Jayaram Hodaya Haimov Sankar Jagadeeshan Dinesh Babu Manikandan Raghda Abu Shareb Livingstone Nurukurti Menachem Sklarz J.Silvio Gutkind Irit Allon Ofir Cohen Moshe Elkabets Etta Livneh 《Signal Transduction and Targeted Therapy》 SCIE CSCD 2026年第3期1633-1652,共20页
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
关键词 genetic ablation studieswe breast cancer PKC eta Triple negative breast cancer Epithelial mesenchymal transition antiapoptotic kinase Hippo YAP signaling pathway Metastasis
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