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

文献类型：期刊论文

作者Wang, Yingying8; Zhang, Youping8; Luo, Hao5,8; Wei, Wei4; Liu, Wanting2; Wang, Weiwei8; Wu, Yunzhao3; Peng, Cheng7; Ji, Yanjie8; Zhang, Jianfang7
刊名ACTA PHARMACEUTICA SINICA B
出版日期2024-12-01
卷号14期号:12页码:5235-5248
关键词Ubiquitin-specific protease 2 KRAS Gambogic acid Multiple myeloma Degradation Ubiquitination Allosteric pocket Deubiquitination
ISSN号2211-3835
DOI10.1016/j.apsb.2024.08.019
英文摘要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 potential 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. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
WOS关键词NF-KAPPA-B ; CANCER ; PROTEIN ; INHIBITION ; PATHWAY ; BINDING ; OLD
资助项目Shanghai Municipal Commission of Health and Family Planning[(2021-2023) -0208] ; Shandong Provincial Natural Science Foundation[ZR2020QH095] ; China Postdoctoral Science Foun-dation[2023M742311] ; Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases ; Core Facility of Basic Medical Sciences, Shanghai Jiao Tong University School of Medicine
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001392280400001
出版者INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/315603]  
专题新药研究国家重点实验室
通讯作者Yang, Yongqing; Xu, Zhijian; Wu, Yingli
作者单位1.Shanghai Jiao Tong Univ, Peoples Hosp 9, Coll Stomatol, Dept Oral & Maxillofacial Head & Neck Oncol,Sch Me, Shanghai 200011, Peoples R China
2.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Sch Med, Shanghai 200025, Peoples R China
3.Univ Cambridge, Yusuf Hamied Dept Chem, Cambridge CB2 1EW, England
4.Anhui Med Univ, Dept Oncol, Affiliated Hosp 1, Hefei 230022, Peoples R China
5.Shandong Second Med Univ, Sch Basic Med Sci, Weifang 261053, Peoples R China
6.Shanghai Univ Tradit Chinese Med, Yueyang Hosp Integrated Tradit Chinese & Western M, Shanghai Res Inst Acupuncture & Meridian, Shanghai 201203, Peoples R China
7.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China
8.Shanghai Jiao Tong Univ, Chem Biol Div Shanghai Univ E Inst, Shanghai Tongren Hosp,Sch Med,Chinese Minist Educ, Hongqiao Int Inst Med,Fac Basic Med,Key Lab Cell D, Shanghai 200025, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Yingying,Zhang, Youping,Luo, Hao,et al. Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells[J]. ACTA PHARMACEUTICA SINICA B,2024,14(12):5235-5248.
APA Wang, Yingying.,Zhang, Youping.,Luo, Hao.,Wei, Wei.,Liu, Wanting.,...&Wu, Yingli.(2024).Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells.ACTA PHARMACEUTICA SINICA B,14(12),5235-5248.
MLA Wang, Yingying,et al."Identification of USP2 as a novel target to induce degradation of KRAS in myeloma cells".ACTA PHARMACEUTICA SINICA B 14.12(2024):5235-5248.

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来源：上海药物研究所

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