1.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
Acta Pharmaceutica Sinica B 2024;14(12):5235-5248
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.
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