State Key Laboratory of Chemical Oncogenomics, Laboratory of Structural Biology and Drug Discovery, Laboratory of Ubiquitination and Targeted Therapy, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
Cell Rep. 2024 Nov 26;43(11):114917. doi: 10.1016/j.celrep.2024.114917. Epub 2024 Nov 4.
RAS oncogenic mutations are pivotal drivers of tumorigenesis. Ubiquitination modulates RAS functions, including activation, stability, and localization. While several E3 ligases regulate RAS ubiquitination, RAS deubiquitination remains less understood. Our study reveals that ubiquitin-specific protease 7 (USP7) directly deubiquitinates KRAS, stabilizing it and promoting the proliferation of non-small cell lung cancer (NSCLC) cells. Mechanistically, USP7 binds KRAS via its TRAF domain and removes the K48-linked polyubiquitin chains from residue K147. In addition, USP7 also stabilizes oncogenic KRAS mutants through deubiquitination. In lung cancer tissues, high USP7 expression is positively correlated with KRAS and is associated with lower patient survival rates. Moreover, USP7 inhibitors suppress NSCLC cell proliferation, particularly in cells resistant to the KRAS-G12C inhibitor AMG510. In conclusion, our findings identify USP7 as a key deubiquitinase regulating RAS stability, and targeting USP7 is a promising strategy to counteract KRAS inhibitor resistance in NSCLC.
RAS 致癌突变是肿瘤发生的关键驱动因素。泛素化调节 RAS 的功能，包括激活、稳定性和定位。虽然有几种 E3 连接酶调节 RAS 的泛素化，但 RAS 的去泛素化仍然知之甚少。我们的研究表明，泛素特异性蛋白酶 7（USP7）直接对 KRAS 进行去泛素化，稳定其结构并促进非小细胞肺癌（NSCLC）细胞的增殖。在机制上，USP7 通过其 TRAF 结构域与 KRAS 结合，并从残基 K147 上去除 K48 连接的多泛素链。此外，USP7 还通过去泛素化稳定致癌性 KRAS 突变体。在肺癌组织中，USP7 的高表达与 KRAS 呈正相关，并与患者生存率降低相关。此外，USP7 抑制剂可抑制 NSCLC 细胞增殖，尤其是在对 KRAS-G12C 抑制剂 AMG510 耐药的细胞中。总之，我们的研究结果表明 USP7 是调节 RAS 稳定性的关键去泛素酶，靶向 USP7 是克服 NSCLC 中 KRAS 抑制剂耐药性的一种有前途的策略。
