Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally express...Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.展开更多
The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulate...The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulated in regenerating airway epithelial clls.To deter.mine the role ofHippo signaling in the lung,the mammalian Hippo kinases,Mst1 and Mst2,were deleted in epithelial cells ofthe embry-onic and mature mouse lung.Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation.The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated followving embryonic Mst1/2 deletion.Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation.Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion,consistent with canonical Hippo/Yap signaling.YAP potentiated cell prolif-eration and inhibited dfferentiation of human bronchial epithelial cells in vitro.Loss of Mst1/2 and expression ofYAP regulated transcrip-tional targets controlling cell proliferation and diferentiation,including Ajuba LIM protein.Ajuba was required forthe effects ofYAP oncell proliferation in vitro.Hippo/Yapsignaling regulates Ajuba and controls proliferation and diferentiation oflung epithelial progenitor cells.展开更多
基金This work was supported by grants from the National Key Research and Development Program of China(2021YFA0909300 to Dong Yin)the National Natural Science Foundation of China(82372617,81972658 and 81802812 to Li Peng,81803636 to Xiaoqing Yuan,82073067 and 81872140 to Dong Yin)+5 种基金Guangdong Basic and Applied Basic Research Foundation(2024B1515020090,2023A1515012683,2019A1515012114 and 2018A030313129 to Li Peng,2024A1515030038 to Xiaoqing Yuan,2021A0505030084 and 2019B020226003 to Dong Yin)Basic and Applied Basic Research of Guangzhou Municipal Basic Research Plan(2024A03J0845 and 2023A04J2098 to Li Peng)National Postdoctoral Program for Innovation Talents(grant no.BX20190395 to Li Peng)China Postdoctoral Science Foundation(grant no.2019M663254 to Li Peng)the Fundamental Research Funds for the Central Universities(grant no.20ykpy105 to Li Peng)the Science and Technology Planning Project of Guangdong Province(2023B1212060013 and 2020B1212030004).
文摘Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.
基金This work was supported by National Heart,Lung,and Blood Institute and Lung Repair and Re generation Consortium(LRRC)U01-110964 to JA.W.and A-K.PLung Map U01-HL122642 to JA.W.,B.R.S..and A-K.P.
文摘The Hippo/Yap pathwayis a wll-conserved signaling cascade that regulates cell proliferation and dfferentiationto control organsize and stem/progenitor cell behavior.Following airway injury,Yap was dynamically regulated in regenerating airway epithelial clls.To deter.mine the role ofHippo signaling in the lung,the mammalian Hippo kinases,Mst1 and Mst2,were deleted in epithelial cells ofthe embry-onic and mature mouse lung.Mst1/2 deletion in the fetal lung enhanced proliferation and inhibited sacculation and epithelial cell differentiation.The transcriptional inhibition of cell proliferation and activation of differentiation during normal perinatal lung maturation were inversely regulated followving embryonic Mst1/2 deletion.Ablation of Mst1/2 from bronchiolar epithelial cells in the adult lung caused airway hyperplasia and altered differentiation.Inhibitory Yap phosphorylation was decreased and Yap nuclear localization and transcriptional targets were increased after Mst1/2 deletion,consistent with canonical Hippo/Yap signaling.YAP potentiated cell prolif-eration and inhibited dfferentiation of human bronchial epithelial cells in vitro.Loss of Mst1/2 and expression ofYAP regulated transcrip-tional targets controlling cell proliferation and diferentiation,including Ajuba LIM protein.Ajuba was required forthe effects ofYAP oncell proliferation in vitro.Hippo/Yapsignaling regulates Ajuba and controls proliferation and diferentiation oflung epithelial progenitor cells.
