CDK4/6 inhibition blocks cancer metastasis through a USP51-ZEB1-dependent deubiquitination mechanism
作者机构:Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular RegulationMedical College of Nankai UniversityTianjin 300071China College of PharmacyNankai UniversityTianjin 300071China Tianjin Key Laboratory of Organ TransplantationTianjin First Center HospitalTianjin 300192China Department of Cancer BiologyWake Forest University School of MedicineWinston-SalemNC 27157USA
出 版 物:《Signal Transduction and Targeted Therapy》 (信号转导与靶向治疗(英文))
年 卷 期:2020年第5卷第1期
页 面:2214-2226页
核心收录:
学科分类:1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金:supported by grants from the National Natural Science Foundation of China(No.81972454 No.81472545 and No.81670600) the Tianjin Natural Science Foundation(No.17JCZDJC36600)
主 题:metastasis CDK4 ubiquitin
摘 要:Tumor metastasis is the most common cause of cancer-related deaths,yet it remains poorly *** transcription factor zinc-finger E-box binding homeobox 1(ZEB1)is involved in the epithelial-to-mesenchymal transition(EMT)and plays a pivotal role in tumor ***,the underlying mechanisms of the posttranslational modification of ZEB1 remain largely ***,we demonstrated that specific inhibition of CDK4/6 was able to block tumor metastasis of breast cancer by destabilizing the ZEB1 protein in vitro and in ***,we determined that the deubiquitinase USP51 is a bona fide target of CDK4/*** phosphorylation and activation of USP51 by CDK4/6 is necessary to deubiquitinate and stabilize ***,we found a strong positive correlation between the expression of p-RB(an indicator of CDK4/6 activity),p-USP51 and ZEB1 in metastatic human breast cancer ***,the high expression of p-RB,p-USP51,and ZEB1 was significantly correlated with a poor clinical *** together,our results provide evidence that the CDK4/6-USP51-ZEB1 axis plays a key role in breast cancer metastasis and could be a viable therapeutic target for the treatment of advanced human cancers.