KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31

Ci Yang; Hong-Xu Li; Hu Gan; Xin Shuai; Chen Dong; Wei Wang; Dandan Lin; Bo Zhong

doi:10.1016/j.devcel.2025.01.015

KRAS4B oncogenic mutants promote non-small cell lung cancer progression via the interaction of deubiquitinase USP25 with RNF31

Dev Cell. 2025 Jun 23;60(12):1768-1783.e5. doi: 10.1016/j.devcel.2025.01.015. Epub 2025 Feb 13.

Authors

Ci Yang¹, Hong-Xu Li², Hu Gan³, Xin Shuai³, Chen Dong⁴, Wei Wang⁵, Dandan Lin⁶, Bo Zhong⁷

Affiliations

¹ Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
² Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
³ Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China.
⁴ School of Medicine, Westlake University, Hangzhou 310024, China.
⁵ Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China. Electronic address: wangwei1018@whu.edu.cn.
⁶ Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China. Electronic address: lindandan@whu.edu.cn.
⁷ Department of Gastrointestinal Surgery, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Department of Virology, College of Life Sciences, State Key Laboratory of Metabolism and Regulation in Complex Organisms, Wuhan University, Wuhan 430072, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China; Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China; Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China. Electronic address: zhongbo@whu.edu.cn.

PMID: 39952242
DOI: 10.1016/j.devcel.2025.01.015

Abstract

Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are genetic drivers in various cancers, including non-small cell lung cancer (NSCLC). However, the regulatory mechanisms underlying the progression of NSCLC driven by oncogenic KRAS mutants are incompletely understood. Here, we show that ubiquitin specific peptidase 25 (USP25) impedes ring finger protein 31 (RNF31)-mediated linear ubiquitination of KRAS oncogenic mutants (KRAS^muts) independently of its deubiquitinase activity, which facilitates the plasma membrane (PM) localization and the downstream oncogenic signaling of KRAS^muts. Importantly, knockout (KO) of USP25 effectively suppresses tumor growth and RAS signaling in KRAS^muts-driven autochthonous NSCLC mouse models and xenograft models, which is restored by additional deletion or inhibition of RNF31. Notably, knockin of USP25^C178A in KRas^G12D-driven NSCLC models fails to inhibit cancer progression and reconstitution of USP25^C178A into USP25 KO A549 cells restores tumor growth. These findings identify previously uncharacterized roles of USP25 and RNF31 in oncogenic KRAS-driven NSCLC progression and provide potential therapeutic targets for KRAS^muts-related cancers.

Keywords: KRAS; MAPK signaling; RNF31; USP25; linear ubiquitination; non-small cell lung cancer.

MeSH terms

A549 Cells
Animals
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Cell Proliferation
Disease Progression
Humans
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Mutation / genetics
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism
Signal Transduction
Ubiquitin Thiolesterase* / genetics
Ubiquitin Thiolesterase* / metabolism
Ubiquitin-Protein Ligases* / genetics
Ubiquitin-Protein Ligases* / metabolism
Ubiquitination

Substances

Proto-Oncogene Proteins p21(ras)
Ubiquitin Thiolesterase
Ubiquitin-Protein Ligases
KRAS protein, human