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

USP7 deubiquitinates KRAS and promotes non-small cell lung cancer

  • Cell Rep. 2024 Nov 4;43(11):114917. doi: 10.1016/j.celrep.2024.114917.
Bin Huang 1,  Dan Cao 1,  Xiao Yuan 2,  Yuxian Xiong 1,  Bingzhang Chen 3,  Yingjie Wang 4,  Xiaogang Niu 5,  Ruijun Tian 2,  Hao Huang 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Chemistry, School of Science, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 3 Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China; College of Chemistry, Jilin University, Changchun 130023, China.
  • 4 Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen 518132, China.
  • 5 College of Chemistry and Molecular Engineering, Beijing Nuclear Magnetic Resonance Center, Peking University, Beijing 100871, China.
  • 6 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; Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518132, China. Electronic address: huang.hao@pku.edu.cn.
PMID: 39499616 DOI: 10.1016/j.celrep.2024.114917
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.

Keywords

AMG510; CP: Cancer; KRAS; NSCLC; RAS; USP7; cancer; deubiquitination; drug resistance; inhibitor; ubiquitin.

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