YAP Inactivation by Soft Mechanotransduction Relieves MAFG for Tumor Cell Dedifferentiation  

作　　者：Jiadi Lv Xiaohan Liu Yabo Zhou Feiran Cheng Haoran Chen Shunshun Li Dianheng Wang Li Zhou Zhenfeng Wang Nannan Zhou Jie Chen Bo Huang 

机构地区：[1]Department of Immunology&State Key Laboratory of Common Mechanism Research for Major Diseases,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences&Peking Union Medical College(PUMC),Beijing,100005,China [2]Department of Histology and Embryology,Basic Medical Cllege,China Medical University,Shenyang,Liaoning 11122,China [3]Department of Immunology,Basic Medical Cllege China Medical University,Shenyang,Liaoning 110122,China [4]Department of Biochemistry&Molecular Biology,Tongji Medical College,Huazhong University of Science&Technology,Wuhan 430030,China

出　　处：《Research》2024年第2期401-415,共15页研究（英文）

基　　金：supported by National Natural Science Foundation of China grant nos.82388201 to B.H.and 82003145 to J.L.;Haihe Laboratory of Cell Ecosystem Innovation Fund grant no.22HHXBSS00009 to B.H.;National Key Research and Development Program of China grant no.2022YFA1206000;CAMS Innovation Fund for Medical Sciences(CIFMS)grant nos.2021-I2M-1-021 and 2022-I2M-JB-008 to B.H.

摘　　要：Solid tumor cells live in a highly dynamic mechanical microenvironment.How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma.Here,we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells.Mechanistically,integrin?was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein(YAP).YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G(MAFG),allowing MAFG to transactivate the stemness genes NANOG,SOX2,and NESTIN.Inactivation also restoredβ8 expression,thereby forming a closed mechanical loop.Importantly,MAFG expression is correlated with worse prognosis.Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation,which has therapeutic implications for exploring innovative strategies to attack malignancies.

关 键 词：ACTIVATION thereby MAF 

分 类 号：R730[医药卫生—肿瘤]