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Identification of taz as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis

National Science Review 2022年第7期9卷 17-31页

作者： Yujuan Jin Qiqi Zhao Weikang Zhu Yan Feng Tian Xiao Peng Zhang Liyan Jiang Yingyong Hou Chenchen Guo Hsinyi Huang Yabin Chen Xinyuan Tong Jiayu Cao Fei Li Xueliang Zhu Jun Qin Dong Gao Xin-Yuan Liu Hua Zhang Luonan Chen Roman K.Thomas Kwok-Kin Wong Lei Zhang Yong Wang Liang Hu Hongbin Ji State Key Laboratory of Cell Biology Chinese Academy of Sciences Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences Center for Excellence in Molecular Cell Science Chinese Academy of Sciences Center for Excellence in Mathematical Sciences National Center for Mathematics and Interdisciplinary Sciences Key Laboratory of ManagementDecision and Information SystemHua Loo-Keng Center for Mathematical Sciences Academy of Mathematics and Systems ScienceChinese Academy of Sciences Shenzhen Key Laboratory of Translational Medicine of Tumor Department of Cell Biology and Genetics Shenzhen University Health Sciences Center Shanghai Pulmonary Hospital Tongji University Shanghai Chest Hospital Shanghai Jiaotong University Zhongshan Hospital Fudan University Department of Pathology School of Basic Medical Sciences Fudan University School of Life Science and Technology Shanghai Tech University CAS Key Laboratory of Tissue Microenvironment and Tumor CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Nutrition and Health SciencesChinese Academy of Sciences Laura and Isaac Perlmutter Cancer Center New York University Langone Medical Center School of Life Science Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences Department of Translational Genomics Center of Integrated Oncology Cologne-BonnMedical FacultyUniversity of Cologne Department of Pathology University Hospital Cologne

Small-cell lung cancer(SCLC) is a recalcitrant cancer characterized by high ***,the exact cell type contributing to metastasis remains *** a Rb1L/L/Trp53L/Lmouse model,we identify the NCAMhiCD44lo/-subpopulation as the SCLC metastasizing cell(SMC),which is progressively transitioned from the non-metastasizing NCAMloCD44hicell(non-SMC).Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex,and knockout of its central component,Brgl,significantly inhibits such phenotypic transition and ***,taz is silenced by the SWI/SNF complex during SCLC malignant progression,and its knockdown promotes SMC transition and ***,ectopic taz expression reversely drives SMC-to-non-SMC transition and alleviates ***-cell RNA-se quencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis,and immunostaining data show a positive correlation between taz and patient *** data uncover high SCLC plasticity and identify taz as the key mole cular switch in orchestrating SCLC phenotypic transition and metastasis.

关键词： small cell lung cancer SWI/SNF complex taz phenotypic transition metastasis

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Regulation of taz in cancer

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Protein & Cell 2016年第8期7卷 548-561页

作者： Xin Zhou Qun-Ying Lei Key Laboratory of Metabolism and Molecular Medicine Ministry of Education and Department of Biochemistry and Molecular Biology and Institutes of Biomedical Sciences Fudan University Shanghai Medical College Shanghai 200032 China Department of Cancer Biology University of Texas MD Anderson Cancer Center Houston TX 77030 USA

taz, a transcriptional coactivator with PDZ-binding motif, is encoded by WWTR1 gene （WW domain containing transcription regulator 1）. taz is tightly regulated in the hippo pathway-dependent and -independent manner in response to a wide range of extracellular and intrinsic signals, including cell density, cell polarity, F-actin related mechanical stress, ligands of G protein-coupled recep- tors （GPCRs）, cellular energy status, hypoxia and osmo- tic stress. Besides its role in normal tissue development, taz plays critical roles in cell proliferation, differentiation, apoptosis, migration, invasion, epithelial-mesenchymal transition （EMT）, and stemness in multiple human cancers. We discuss here the regulators and regulation of TAT. We also highlight the tumorigenic roles of taz. and its potential therapeutic impact in human cancers.

关键词： taz the Hippo pathway cancer

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taz and myostatin involved in muscle atrophy of congenital neurogenic clubfoot

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World Journal of Clinical Cases 2019年第16期7卷 2238-2246页

作者： Jia-Xing Sun Ze-Yu Yang Li-Mei Xie Bing Wang Ning Bai Ai-Lu Cai Department of Ultrasound Shengjing Hospital of China Medical UniversityShenyang 110004Liaoning ProvinceChina Key Laboratory of Medical Cell Biology Ministry of EducationInstitute of Translational MedicineChina Medical UniversityLiaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and PreventionShenyang 110004Liaoning ProvinceChina

BACKGROUND Muscular atrophy is the basic defect of neurogenic *** atrophy of clubfoot needs more scientific and reasonable imaging measurement parameters to *** Hippo pathway and myostatin pathway may be directly correlated in *** this study,we will use congenital neurogenic clubfoot muscle atrophy model to verify in ***,the antagonistic mechanism of taz on myostatin was studied in the C2C12 cell differentiation *** To identify muscle atrophy in fetal neurogenic clubfoot by ultrasound imaging and detect the expression of taz and myostatin in gastrocnemius *** elucidate the possible mechanisms by which taz antagonizes myostatin-induced atrophy in an in vitro cell *** Muscle atrophy in eight cases of fetal unilateral clubfoot with nervous system abnormalities was identified by 2D and 3D *** blotting and immunostaining were performed to detect expression of myostatin and *** overexpression in C2C12 myotubes and the expression of associated proteins were analyzed by western *** The maximum cross-sectional area of the fetal clubfoot on the varus side was reduced compared to the contralateral *** was elevated in the atrophied gastrocnemius muscle,while taz expression was *** were negatively *** overexpression reversed the diameter reduction of the myotube,downregulated phosphorylated Akt,and increased the expression of forkhead box O4 induced by *** Ultrasound can detect muscle atrophy of fetal *** and myostatin are involved in the pathological process of neurogenic clubfoot muscle *** antagonizes myostatin-induced myotube atrophy,potentially through regulation of the Akt/forkhead box O4 signaling pathway.

关键词： Congenital clubfoot Neurogenic Muscle atrophy Myostatin taz

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A YAP/taz-CD54 axis is required for CXCR2-CD44-tumor-specific neutrophils to suppress gastric cancer

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Protein & Cell 2023年第7期14卷 515-533页

作者： Pingping Nie Weihong Zhang Yan Meng Moubin Lin Fenghua Guo Hui Zhang Zhenzhu Tong Meng Wang Fan Chen Liwei An Yang Tang Yi Han Ruixian Yu Wenjia Wang Yuanzhi Xu Linxin Wei Zhaocai Zhou Shi Jiao CAS Center for Excellence in Molecular Cell Science Institute of Biochemistry and Cell BiologyShanghai Institutes for Biological SciencesChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 200031China State Key Laboratory of Genetic Engineering School of Life SciencesZhongshan HospitalFudan UniversityShanghai 200438China Tongji University Cancer Center Department of Medical UltrasoundShanghai Tenth People's HospitalUltrasound Research and Education InstituteTongji University School of MedicineShanghai200072China Postdoctoral Station of Clinical Medicine Shanghai Tenth People's HospitalTongji University School of MedicineShanghai 200072China Tumor Immunology and Gene Therapy Center Shanghai Eastem Hepatobiliary Surgery HospitalShanghai 200438China Department of General Surgery Yangpu HospitalTongji University School of MedicineShanghai 200090China Department of General Surgery Hua'shan HospitalFudan University Shanghai Medical CollegeShanghai 200040China Department of Stomatology Shanghai Tenth People's HospitalTongji University School of MedicineShanghai 200072China Collaborative Innovation Center for Cancer Personalized Medicine School of Public HealthNanjing Medical UniversityNanjing 211166China

As an important part of tumor microenvironment,neutrophils are poorly understood due to their spatiotemporal heterogeneity in *** we defined,at single-cell resolution,CD44-CxCR2-neutrophils as tumor-specific neutrophils(tsNeus)in both mouse and human gastric cancer(GC).We uncovered a Hippo regulon in neutrophils with unique YAP signature genes(e.g.,ICAM1,CD14,EGR1)distinct from those identified in epithelial and/or cancer ***,knockout of YAP/taz in neutrophils impaired their differentiation into CD54+tsNeus and reduced their antitumor activity,leading to accelerated GC ***,the relative amounts of CD54+tsNeus were found to be negatively associated with GC progression and positively associated with patient ***,GC patients receiving neoadjuvant chemotherapy had increased numbers of CD54+***,pharmacologically enhancing YAP activity selectively activated neutrophils to suppress refractory GC,with no significant inflammation-related side ***,our work characterized tumor-specific neutrophils in GC and revealed an essential role of YAP/taz-CD54 axis in tsNeus,opening a new possibility to develop neutrophil-based antitumor therapeutics.

关键词： neutrophils YAP taz gastriccancer

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USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing taz

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Cellular & Molecular Immunology 2023年第3期20卷 252-263页

作者： Xiaotong Zhu Peng Wang Xiaoxia Zhan Yuping Zhang Junli Sheng Shitong He Yitian Chen Dingnai Nie Xiaolong You Haiyan Mai Qinghong Yu Laisheng Li Ligang Jie Shengfeng Hu Department of Rheumatology and Clinical Immunology Zhujiang HospitalSouthern Medical UniversityGuangzhouChina Department of Emergency Medicine Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhouChina Department of Laboratory Medicine The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdongChina Institute of Molecular Immunology School of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouGuangdongChina Provincial Key Laboratory of Immune Regulation and Immunotherapy School of Laboratory Medicine and BiotechnologySouthern Medical UniversityGuangzhouGuangdongChina

The balance between inflammatory T helper type 17(Th17)and immunosuppressive regulatory T(Treg)cells is critical for maintaining immune homeostasis in the human body and is tightly regulated under healthy *** increasing number of studies have reported that deubiquitinases(DUBs)play a vital role in regulating Th17-and Treg-cell ***,the biological functions of only a small fraction of DUBs in Th17-and Treg-cell differentiation are well *** this study,we identified ubiquitin-specific peptidase 1(USP1)as a vital regulator of CD4+T-cell ***1 promoted Th17-cell differentiation but attenuated Treg-cell differentiation,thereby promoting the development of inflammatory ***,USP1 in CD4+T cells enhanced the activity of RORγt but promoted the proteasomal degradation of Foxp3 through deubiquitination and stabilization of taz in vitro and in ***,ML323,a specific inhibitor of the USP1/UAF1 deubiquitinase complex,inhibited Th17-cell differentiation and promoted Treg-cell differentiation in vitro and in vivo,indicating that ML323 might be a promising candidate for the treatment of diseases associated with an imbalance between Th17 and Treg *** study highlights the critical role of USP1 in regulating adaptive immune responses and suggests that USP1 might be a drug target for the treatment of diseases associated with an imbalance between Th17 and Treg cells.

关键词： USP1 taz Th17 Treg

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NDFIP1 limits cellular taz accumulation via exosomal sorting to inhibit NSCLC proliferation

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Protein & Cell 2023年第2期14卷 123-136页

作者： Yirui Cheng Xin Lu Fan Li Zhuo Chen Yanshuang Zhang Qing Han Qingyu Zeng Tingyu Wu Ziming Li Shun Lu Cecilia Williams Weiliang Xia State Key Laboratory of Oncogenes and Related Genes Ren Ji HospitalSchool of Medicine and School of Biomedical EngineeringShanghai Jiao Tong UniversityShanghai 200030China Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200092China Shanghai Lung Cancer Center Shanghai Chest HospitalShanghai Jiao Tong UniversityShanghai 200030China Department of Protein Science KTH Royal Institute of TechnologyScience for Life LaboratorySolna 17070Sweden

NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still ***,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into ***,whether WW domain-containing transcription regulator 1(WWTR1,also known as taz)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any ***,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter ***,we confirmed the interaction between taz and NDFIP1,and the existence of taz in exosomes,which requires ***,knockout of NDFIP1 led to taz accumulation with no change in its mRNA level and degradation *** the cellular taz level could be altered by exosome ***,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing taz eliminated the increase of proliferation caused by NDFIP1 ***,taz was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal taz level was lower in NSCLC *** summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of taz.

关键词： NDFIP1 taz NSCLC exosome cargo sorting

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Yes-associated protein(YAP)and transcriptional coactivator with a PDZ-binding motif(taz):a nexus between hypoxia and cancer

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Acta Pharmaceutica Sinica B 2020年第6期10卷 947-960页

作者： Chenxi Zhao Chenming Zeng Song Ye Xiaoyang Dai Qiaojun He Bo Yang Hong Zhu Zhejiang Province Key Laboratory of Anti-Cancer Drug Research College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Department of Hepatobiliary and Pancreatic Surgery the Second Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310009China Center for Drug Safety Evaluation and Research of Zhejiang University Hangzhou 310058China

Hypoxia is a common feature of solid *** transcription factors,hypoxia-inducible factors(HIFs)are the master regulators of the hypoxic microenvironment;their target genes function in tumorigenesis and tumor ***,both yes-associated protein(YAP)and its paralog transcriptional coactivator with a PDZ-binding motif(taz)play fundamental roles in the malignant progression of hypoxic *** downstream effectors of the mammalian Hippo pathway,YAP and/or taz(YAP/taz)are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2(LATS1/2)-MOB kinase activator 1(MOB 1)complex,which restricts the transcriptional activity of YAP/***,dephosphorylated YAP/taz have the ability to translocate to the nucleus where they induce transcription of target genes,most of which are closely related to *** we review the tumor-related signaling crosstalk between YAP/taz and hypoxia,describe current agents and therapeutic strategies targeting the hypoxia-YAP/taz axis,and highlight questions that might have a potential impact in the future.

关键词： YAP taz HIFs Hypoxia Solid tumor

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Evaluation of taz expression and its effect on tumor invasion and metastasis in human glioma

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Asian Pacific Journal of Tropical Medicine 2014年第10期7卷 757-760页

作者： Pei-Dong Li Xin Jun Wang Qiao Shan Yue-Hui Wu Zhen Wang Department of Neurosurgery the Fifth Affiliated Hospital of Zhengzhou University

Objective:To evaluate the expression taz and its role in tumor invasion and metastetsis in human ***:The expression of taz protein was measured in 48 samples of surgically resected human glioma and 13 samples of normal brain tissues using *** was knocked down by a retrovirus-mediated taz shRNA in a glioma cell *** cell migration and invasion assays were used to determine migration and invasion of SNB19 ***:The positive expression tale of taz protein in glioma tissnes was significantly higher than than in normal brain tissues(79.2%vs.15.4%.Ptaz protein in poorly differentiated tumor tissues was significantly higher as compared with that in well differentiated tissues(96.0%vs.60.9%,Ptaz was significantly knocked down by taz shRNA(Ptaz knockdown significantly reduced cell migration and invasion(Ptaz protein overexpression is observed in human glioma and its elevated expression is significantly correlated with poor *** knockdown prominently reduces cell migration and invasion in SNB19 cells,suggesling that taz may play a key role in the initiation and progression of human glioma.

关键词： taz Glioma Clinical significance Metastasis Invasion

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Hemodynamic Shear Stress Regulates the Survival of Circulating Tumour Cells Through Piezo1-Actomyosin-Mediated YAP/taz Nuclear Translocation

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医用生物力学 2019年第A1期34卷 130-131页

作者： Keming Li Ying XIN Kai Tang Youhua Tan The Hong Kong Polytechnic University Shenzhen Research Institute ShenzhenChina Department of BiomedicalEngineering Hong Kong Polytechnic UniversityHong KongChina

It is critical to combat tumor metastasis by eradicating disseminated tumor cells in any step during the metastasis *** entering the blood circulation system,tumor cells are in suspension and experience considerable levels of fluid shear ***,the influence of hemodynamic shear stress on the survival of CTCs and the underlying mechanotransduction mechanisms remain *** study shows that fluid shear stress can eliminate the majority of CTCs and the viability of suspended tumor cells depends on the stress magnitude,indicating that tumor cells can sense and respond to fluid shear ***,the expression of Piezo1 but not Piezo2 is greatly upregulated in suspended tumor cells after shear stress ***/activating Piezo1 increases/decreases the viability of suspended tumor cells in shear flow,which depends on Piezo1-mediated calcium *** findings suggest that Piezo1 may be the major mechanosensor by which suspended tumor cells sense fluid shear *** the downstream effector of Piezo1,actomyosin in tumor cells is significantly activated under increasing shear *** activity influences the survival of CTCs in shear flow and rescues the effects of Piezo1 on tumor cell survival,suggesting that hemodynamic shear stress regulates the survival of CTCs through Piezo1 mediated actomyosin ***,fluid shear stress considerably up-regulates YAP/taz activity of suspended tumor cells and promotes their nuclear translocation in a magnitude-dependent *** YAP/taz enhances the viability of suspended tumor cells in shear stress,while activating their activity decreases tumor cell survival,suggesting that YAP/taz activation promotes the apoptosis of suspended tumor cells,which is different from the findings that YAP/taz facilitates the survival of adherent cells to shear ***,blocking the nuclear import of YAP/taz inactivates the sensation of suspended tumor cells to fluid shear flow an

关键词： Hemodynamic Shear Stress Circulating Tumour Cells YAP/taz Nuclear Translocation taz

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Hippo signaling activates hedgehog signaling by taz-driven Gli3 processing

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Cell Regeneration 2023年第1期12卷 407-422页

作者： Chao Tang Jirong Wang Minli Yao Xing Ji Wei Shi Chengyun Xu Ling-Hui Zeng Ximei Wu Department of Pharmacology Zhejiang University School of Medicine866 Yuhangtang Rd.Hangzhou 310058China National Clinical Research Center for Child Health of the Children’s Hospital Zhejiang University School of MedicineHangzhou 310052China Translational Research Program in Pediatric Orthopaedics The Children’s Hospital of PhiladelphiaPhiladelphiaPA 19104USA Department of Pharmacology Zhejiang University City College51 Huzhou StreetHangzhou 310015China Department of Orthopeadic Surgery Sir Run Run Shaw HospitalZhejiang University School of MedicineHangzhou 310016China

The overlapping roles of Hippo and Hedgehog signaling in biological functions and diseases prompt us to inves-tigate their potential *** of Hippo signaling enhances the transcriptional output of Hedgehog signaling,and the role of Hippo signaling in regulating Hedgehog signaling relies on the Hippo pathway key effector,***,taz exhibits a gradient expression across the posterior-to-anterior of limb bud mesoderms,similar to Sonic hedgehog(Shh).Importantly,taz drives PKA to phosphorylate Gli3,resulting in the Gli3 processing into its repressor and attenuation of Hedgehog signaling in the Shh-independent ***,taz deletion in mouse embryonic limb bud mesenchyme not only enhances the Hedgehog signaling but partially restores the phenotypes from Shh deletion in causing severe defects of anteroposterior patterning and digit number and ***,these results uncover taz-dependent Gli3 processing as a hitherto uncharacterized mechanism controlling Hedgehog signaling,highlighting its cross-regulation by Hippo signaling.

关键词： Hedgehog Hippo taz Gli Limb development

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