RNF6 promotes myeloma cell proliferation and survival by inducing glucocorticoid receptor polyubiquitination  

作　　者：Ying Ren Xin Xu Chen-yu Mao Kun-kun Han Yu-jia Xu Bi-yin Cao Zu-bin Zhang Gautam Sethi Xiao-wen Tang Xin-liang Mao 

机构地区：[1]Department of Pharmacology,College of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China [2]School of Medicine,South University of Science and Technology,Shenzhen 518055,China [3]Department of Pharmacology,Yong Loo Lin School of Medicine,National University of Singapore,Singapore 117600,Singapore [4]National Clinical Research Center for Hematologic Diseases,Jiangsu Institute of Hematology,The First Affiliated Hospital of Soochow University,Suzhou 215100,China [5]Protein Modification and Degradation Key Lab of Guangzhou and Guangdong,School of Basic Medical Sciences,Affiliated Cancer Hospital and Institute of Guangzhou Medical University,Guangzhou 511436,China

出　　处：《Acta Pharmacologica Sinica》2020年第3期394-403,共10页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China(81770154 and 81320108023 to XLM;81873443 to XWT);the Natural Science Foundation of Jiangsu Higher Education Institutes of China(17KJA180010 to XLM,19KJA210002 to XWT);Frontier Clinical Technical Project of the Science and Technology Department of Jiangsu Province(BE2017655 to XWT);The Jiangsu Provinicial Medical Talent(ZDRCA2016045 to XWT);the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD).

摘　　要：RNF6,a RING-type ubiquitin ligase,has been identified as an oncogene in various cancers but its role in multiple myeloma(MM)remains elusive.In the present study we first showed that the expression levels of RNF6 in MM were significantly elevated compared with the bone marrow cells of healthy donors.Overexpression of RNF6 in LP1 and PRMI-8266 MM cell lines promoted cell proliferation,whereas knockdown of RNF6 led to apoptosis of MM cells.Furthermore,we revealed that RNF6,as a ubiquitin ligase,interacted with glucocorticoid receptor(GR)and induced its K63-linked polyubiquitination.Different from current knowledge,RNF6 increased GR stability at both endogenous and exogenous contexts.Such an action greatly promoted GR transcriptional activity,which was confirmed by luciferase assays and by the increased expression levels of prosurvival genes including Bcl-xL and Mcl-1,two typical downstream genes of the GR pathway.Consistent with these findings,ectopic expression of RNF6 in MM cells conferred resistance to dexamethasone,a typical anti-myeloma agent.In conclusion,we demonstrate that RNF6 promotes MM cell proliferation and survival by inducing atypical polyubiquitination to GR,and RNF6 could be a promising therapeutic target for the treatment of MM.

关 键 词：multiple MYELOMA RNF6 GLUCOCORTICOID receptor UBIQUITIN-PROTEASOME pathway apoptosis DEXAMETHASONE 

分 类 号：R96[医药卫生—药理学]