Deubiquitinase USP28 inhibits ubiquitin ligase KLHL2-mediated uridine-cytidine kinase 1 degradation and confers sensitivity to 5'-azacytidine-resistant human leukemia cells  

作　　者：Zhang Heng Huang He Feng Xing Song Huirven Zhang Zhiyong Shen Aizong Qiu Xingfeng 

机构地区：[1]Department of Histology and Embryology,Xiang Ya School of Medicine,Central South University,Changsha 410083,China [2]The Affiliated Hospital of Guilin Medical University,Guangxi Key Laboratory of Brain and Cognitive Neuroscience,Guangxi Neurological Diseases Clinical Research Center [3]Department of Cardiology,Jiading District Central Hospital Affiliated Shanghai University of Medicine&Health Sciences [4]National Center for International Research of Biological Targeting Diagnosis and Therapy(Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research),Guangxi Medical University [5]Department of Surgery,Robert-Wood-Johnson Medical School University Hospital,The State University of New Jersey,New Brunswick,New Jersey,USA [6]Pharmacy Department,The First Affiliated Hospital of USTC,Dirvision of Life Sciences and Medicine,University of Science and Technology of China [7]Department of Gastrointestinal Surgery,Zhongshan Hospital of Xiamen University

出　　处：《解剖学杂志》2021年第S01期168-168,共1页Chinese Journal of Anatomy

摘　　要：Resistance to the chemotherapeutic drug 5'-azacytidine(5'-AZA)is a major obstacle in the treatment of patients with acute myeloid leukemia(AML).The uridine-cytidine kinase 1(UCK1)has an established role in activating 5'-AZA and its protein level is significantly downregulated in patients resistant to the drug.However,the underlying molecular mechanism for the reduced UCK1 expression remains to be elucidated.We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation.We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1.We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization.Conversely,UCK1 phosphorylation by 5'-AZA-activated ATM enhanced the KLHL2-UCK1 complex formation,Importantly,silencing KLHL2 or USP28 overexpression not only inhibited AML cell proliferation but also sensitized AML cells to 5'-AZA-induced apoptosis in vitro and in vivo.These results were no longer observed in USP28-deficient cells.

关 键 词：UBIQUITIN KLH MEDIATED 

分 类 号：R73[医药卫生—肿瘤]