USP7 deubiquitinates KRAS and promotes non-small cell lung cancer.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-11-04 DOI:10.1016/j.celrep.2024.114917

Bin Huang, Dan Cao, Xiao Yuan, Yuxian Xiong, Bingzhang Chen, Yingjie Wang, Xiaogang Niu, Ruijun Tian, Hao Huang

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引用次数: 0

Abstract

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.

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USP7 去泛素化 KRAS 并促进非小细胞肺癌的发生。

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 连接酶调控 RAS 泛素化，但对 RAS 去泛素化的了解仍然较少。我们的研究发现，泛素特异性蛋白酶7（USP7）可直接去泛素化KRAS，使其稳定并促进非小细胞肺癌（NSCLC）细胞的增殖。从机理上讲，USP7 通过其 TRAF 结构域与 KRAS 结合，并从残基 K147 上去除与 K48 链接的多泛素链。此外，USP7 还能通过去泛素化稳定致癌 KRAS 突变体。在肺癌组织中，USP7 的高表达与 KRAS 呈正相关，并与较低的患者生存率有关。此外，USP7 抑制剂可抑制 NSCLC 细胞增殖，尤其是对 KRAS-G12C 抑制剂 AMG510 有抗药性的细胞。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化酶，靶向 USP7 是对抗 NSCLC 中 KRAS 抑制剂耐药性的一种有前途的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.