USP7 deubiquitinates KRAS and promotes non-small cell lung cancer

• DOI: 10.1016/j.celrep.2024.114917
• Publication Date: 2024-11-04T21:03:58Z
• Authors: Bin Huang; Dan Cao; Xiao Yuan; Yuxian Xiong; Bingzhang Chen; Yingjie Wang; Xiaogang Niu; Ruijun Tian; Hao Huang

RAS oncogenic mutations are pivotal drivers of tumorigenesis. Ubiquitination modulates functions, including activation, stability, and localization. While several E3 ligases regulate ubiquitination, deubiquitination remains less understood. Our study reveals that ubiquitin-specific protease 7 (USP7) directly deubiquitinates KRAS, stabilizing it promoting the proliferation non-small cell lung cancer (NSCLC) cells. Mechanistically, USP7 binds KRAS via its TRAF domain removes K48-linked polyubiquitin chains from residue K147. In addition, also stabilizes mutants through deubiquitination. tissues, high expression is positively correlated with associated lower patient survival rates. Moreover, inhibitors suppress NSCLC proliferation, particularly in cells resistant to KRAS-G12C inhibitor AMG510. conclusion, our findings identify as a key deubiquitinase regulating targeting promising strategy counteract resistance NSCLC.