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

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

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

Author: Yingying WANG ¹ ; Youping ZHANG ¹ ; Hao LUO ¹ ; Wei WEI ² ; Wanting LIU ³ ; Weiwei WANG ¹ ; Yunzhao WU ⁴ ; Cheng PENG ⁵ ; Yanjie JI ¹ ; Jianfang ZHANG ⁵ ; Chujiao ZHU ¹ ; Wenhui BAI ¹ ; Li XIA ¹ ; Hu LEI ¹ ; Hanzhang XU ¹ ; Leimiao YIN ⁶ ; Wei WENG ¹ ; Li YANG ¹ ; Ligen LIU ¹ ; Aiwu ZHOU ¹ ; Yueyue WEI ⁵ ; Qi ZHU ⁷ ; Weiliang ZHU ⁵ ; Yongqing YANG ⁶ ; Zhijian XU ⁵ ; Yingli WU ¹
Author Information

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 Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
3. Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
4. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
5. State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
6. 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.
7. 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.
Publication Type:Journal Article
Keywords: Allosteric pocket; Degradation; Deubiquitination; Gambogic acid; KRAS; Multiple myeloma; Ubiquitin-specific protease 2; Ubiquitination
From: Acta Pharmaceutica Sinica B 2024;14(12):5235-5248
CountryChina
Language:English
Abstract: 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.