Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells  

作　　者：Yingying Wang Youping Zhang Hao Luo Wei Wei Wanting Liu Weiwei Wang Yunzhao Wu Cheng Peng Yanjie Ji Jianfang Zhang Chujiao Zhu Wenhui Bai Li Xia Hu Lei Hanzhang Xu Leimiao Yin Wei Weng Li Yang Ligen Liu Aiwu Zhou Yueyue Wei Qi Zhu Weiliang Zhu Yongqing Yang Zhijian 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]State Key Laboratory of Drug Research,Drug Discovery and Design Center,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]Shanghai Research Institute of Acupuncture and Meridian,Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China [4]School of Basic Medical Sciences,Shandong Second Medical University,Weifang 261053,China [5]Department of Oncology,the First Affiliated Hospital of Anhui Medical University,Hefei 230022,China [6]Yusuf Hamied Department of Chemistry,University of Cambridge,Cambridge CB21EW,UK [7]Shanghai Chest Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [8]Department of Oral and Maxillofacial-Head and Neck Oncology,Ninth People’s Hospital,College of Stomatology,Shanghai Jiao Tong University School of Medicine,Shanghai 200011,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第12期5235-5248,共14页药学学报（英文版）

基　　金：supported in part by grants from the National Natural Science Foundation of China(82170145,82322067,82100156,and 82374583);CAMS Innovation Fund for Medical Sciences(CIFMS):2019-I2M-5-051;Shanghai Science and Technology Commission(20ZR1430600,20JC1410100);Shanghai Municipal Commission of Health and Family Planning,NO.ZY(2021-2023)-0208;Shandong Provincial Natural Science Foundation(ZR2020QH095);China Postdoctoral Science Foundation funded project(2023M742311).

摘　　要：Inducing the degradation of KRAS represents a novel strategy to combat cancers with KRAS mutation.In this study,we identify ubiquitin-specific protease 2(USP2)as a novel deubiquitinating enzyme of KRAS in multiple myeloma(MM).Specifically,we demonstrate that gambogic acid(GA)forms a covalent bond with the cysteine 284 residue of USP2 through an allosteric pocket,inhibiting its deubiquitinating activity.Inactivation or knockdown of USP2 leads to the degradation of KRAS,resulting in the suppression of MM cell proliferation in vitro and in vivo.Conversely,overexpressing USP2 stabilizes KRAS and partially abrogates GA-induced apoptosis in MM cells.Furthermore,elevated USP2 levels may be associated with poorer prognoses in MM patients.These findings highlight the po-tential of the USP2/KRAS axis as a therapeutic target in MM,suggesting that strategically inducing KRAS degradation via USP2 inhibition could be a promising approach for treating cancers with KRAS mutations.

关 键 词：Ubiquitin-specific protease 2 KRAS Gambogic acid Multiple myeloma DEGRADATION UBIQUITINATION Allosteric pocket DEUBIQUITINATION 

分 类 号：R733.3[医药卫生—肿瘤]