Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic...Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.展开更多
基金support from the members of the Chilab.We acknowledge the financial support in part by DOD(grant numbers W81XWH-17-1-0143,W81XWH-15-1-0486,W81XWH-19-1-0842)NIH(grant numbers GM124062,1R01NS111588-01A1).
文摘Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.
