Blockade of deubiquitinase YOD1 degrades oncogenic PML/RARα and eradicates acute promyelocytic leukemia cells  

作　　者：Xuejing Shao Yingqian Chen Wei Wang Wenxin Du Xingya Zhang Minyi Cai Shaowei Bing Ji Cao Xiaojun Xu Bo Yang Qiaojun He Meidan Ying 

机构地区：[1]Institute of Pharmacology and Toxicology,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research,College of Pharmaceutical Sciences,Zhejiang University,Hangzhou 310058,China [2]Children’s Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310052,China [3]Cancer Center,Zhejiang University,Hangzhou 310058,China [4]Innovation Institute for Artificial Intelligence in Medicine,Zhejiang University,Hangzhou 310058,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第4期1856-1870,共15页药学学报（英文版）

基　　金：This work was supported by grants from the National Natural Science Foundation of China(No.81973354 to Meidan Ying);China Postdoctoral Science Foundation(No.2020T130593 to Xuejing Shao);Leading Talent of“Ten Thousand Plan”-National High-Level Talents Special Support Plan and the Fundamental Research Funds for the Central Universities(China).

摘　　要：In most acute promyelocytic leukemia(APL)cells,promyelocytic leukemia(PML)fuses to retinoic acid receptor α (RARα)due to chromosomal translocation,thus generating PML/RARαoncoprotein,which is a relatively stable oncoprotein for degradation in APL.Elucidating the mechanism regulating the stability of PML/RARαmay help to degrade PML/RARαand eradicate APL cells.Here,we describe a deubiquitinase(DUB)-involved regulatory mechanism for the maintenance of PML/RARαstability and develop a novel pharmacological approach to degrading PML/RARαby inhibiting DUB.We utilized a DUB siRNA library to identify the ovarian tumor protease(OTU)family member deubiquitinase YOD1 as a critical DUB of PML/RARα.Suppression of YOD1 promoted the degradation of PML/RARα,thus inhibiting APL cells and prolonging the survival time of APL cell-bearing mice.Subsequent phenotypic screening of small molecules allowed us to identify ubiquitin isopeptidase inhibitor I(G5)as the first YOD1 pharmacological inhibitor.As expected,G5 notably degraded PML/RARαprotein and eradicated APL,particularly drug-resistant APL cells.Importantly,G5 also showed a strong killing effect on primary patient-derived APL blasts.Overall,our study not only reveals the DUB-involved regulatory mechanism on PML/RARαstability and validates YOD1 as a potential therapeutic target for APL,but also identifies G5 as a YOD1 inhibitor and a promising candidate for APL,particularly drug-resistant APL treatment.

关 键 词：Acute promyelocytic leukemia PML/RARa Deubiquitinase YOD1 DEGRADATION Drug resistance INHIBITOR THERAPY 

分 类 号：R733.71[医药卫生—肿瘤]