USP7 deubiquitinates KRAS and promotes non-small cell lung cancer

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

doi:10.1016/j.celrep.2024.114917

USP7 deubiquitinates KRAS and promotes non-small cell lung cancer

Cell Rep. 2024 Nov 26;43(11):114917. doi: 10.1016/j.celrep.2024.114917. Epub 2024 Nov 4.

Authors

Bin Huang¹, Dan Cao¹, Xiao Yuan², Yuxian Xiong¹, Bingzhang Chen³, Yingjie Wang⁴, Xiaogang Niu⁵, Ruijun Tian², Hao Huang⁶

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.

MeSH terms

Aminopyridines
Animals
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Cell Proliferation*
HEK293 Cells
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Mice, Nude
Mutation / genetics
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism
Thiocyanates
Thiophenes
Ubiquitin-Specific Peptidase 7* / genetics
Ubiquitin-Specific Peptidase 7* / metabolism
Ubiquitination*

Substances

Ubiquitin-Specific Peptidase 7
Proto-Oncogene Proteins p21(ras)
KRAS protein, human
USP7 protein, human
2,6-diaminopyridine-3,5-bis(thiocyanate)
1-(5-((2,4-difluorophenyl)thio)-4-nitrothiophen-2-yl)ethanone
Aminopyridines
Thiocyanates
Thiophenes