Hsp90/C terminal Hsc70-interacting protein regulates the stability of Ikaros in acute myeloid leukemia cells  

作　　者：Meng Liu Jin Jin Yanjie Ji Huizhuang Shan Zhihui Zou Yang Cao Li Yang Ligen Liu Li Zhou Hu Lei Yunzhao Wu Hanzhang Xu Yingli Wu 

机构地区：[1]Hongqiao International Institute of Medicine,Shanghai Tongren Hospital/Faculty of Basic Medicine,Chemical Biology Division of Shanghai Universities E-Institutes,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Department of Ultrasound,Second Affiliated Hospital of Zhejiang University,Hangzhou 310009,China [3]Department of Hematology,The Third Affiliated Hospital of Soochow University,Changzhou 213003,China [4]Shanghai Institute of Hematology,State Key Laboratory of Medical Genomics,National Research Center for Translational Medicine at Shanghai,Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China

出　　处：《Science China(Life Sciences)》2021年第9期1481-1490,共10页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2017YFA0505200);Science and Technology Committee of Shanghai(19ZR1428700,20ZR1430600);the National Natural Science Foundation of China(81272886,81570118,81570112,81700157,81700475)。

摘　　要：The stability of Ikaros family zinc finger protein 1(Ikaros),a critical hematopoietic transcription factor,can be regulated by cereblon(CRBN)ubiquitin ligase stimulated by immunomodulatory drugs in multiple myeloma.However,other stabilization mechanisms of Ikaros have yet to be elucidated.In this study,we show that the pharmacologic inhibition or knockdown of Hsp90 downregulates Ikaros in acute myeloid leukemia(AML)cells.Proteasome inhibitor MG132 but not autophagy inhibitor chloroquine could suppress the Hsp90 inhibitor STA-9090-induced reduction of Ikaros,which is accompanied with the increased ubiquitination of Ikaros.Moreover,Ikaros interacts with E3 ubiquitin-ligase C terminal Hsc70 binding protein(CHIP),which mediates the STA-9090-induced ubiquitination of Ikaros.In addition,the knockdown of Ikaros effectively inhibits the proliferation of leukemia cells,but this phenomenon could be rescued by Ikaros overexpression.Collectively,our findings indicate that the interplay between HSP90 and CHIP regulates the stability of Ikaros in AML cells,which provides a novel strategy for AML treatment through targeting the HSP90/Ikaros/CHIP axis.

关 键 词：IKAROS CHIP HSP90 AML STA-9090 

分 类 号：R733.71[医药卫生—肿瘤]