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Deubiquitination of ETV4 by USP7 Promotes NSCLC Tumorigenesis via MAPK7 Activation

Xue Meng1,2,3, Jiaxi Zhang1,2, Ning Zhang4,5

  • 1Department of Pathology, Hebei Medical University, Shijiazhuang, Hebei, China, hebmu.edu.cn.

Human Mutation
|May 8, 2026
PubMed

Insights

Ubiquitin-specific protease 7 (USP7) stabilizes ETS variant transcription factor 4 (ETV4) in non-small cell lung cancer (NSCLC). USP7 inhibition reduces ETV4 activity, cell proliferation, and tumor growth, offering a potential therapeutic strategy for NSCLC.

Area of Science:

  • Molecular Oncology
  • Cancer Cell Biology
  • Ubiquitin-Mediated Protein Regulation

Background:

  • Transcriptional dysregulation drives cancer proliferation and metabolic adaptation.
  • Overexpression of ETS variant transcription factor 4 (ETV4) correlates with poor prognosis in non-small cell lung cancer (NSCLC).
  • The role of deubiquitination in regulating ETV4 stability and function in NSCLC remains unclear.

Purpose of the Study:

  • To investigate the role of ubiquitin-specific protease 7 (USP7) in the deubiquitination and regulation of ETV4 in NSCLC.
  • To determine the impact of USP7-mediated ETV4 regulation on the mitogen-activated protein kinase 7 (MAPK7)/extracellular signal-regulated kinase 5 (ERK5) pathway and NSCLC progression.
  • To evaluate USP7 as a potential therapeutic target in NSCLC.

Main Methods:

  • Analysis of ETV4 expression and its correlation with USP7 and MAPK7 in NSCLC datasets.
  • In vitro studies using NSCLC cells to assess the effect of USP7 inhibition on ETV4 ubiquitination, stability, and transcriptional activity.
  • In vivo experiments using a USP7 inhibitor (P22077) to evaluate its impact on tumor growth.
  • Correlation analysis of ETV4, USP7, and ERK5 protein levels with patient prognosis.

Main Results:

  • USP7 deubiquitinates ETV4, protecting it from proteasomal degradation in NSCLC cells.
  • ETV4 transcriptionally regulates MAPK7/ERK5, a key pathway involved in cell proliferation.
  • USP7 inhibition attenuates ETV4-MAPK7-induced cell proliferation and tumor growth.
  • Elevated ETV4, USP7, and ERK5 expression are associated with poor NSCLC prognosis.

Conclusions:

  • USP7 stabilizes ETV4 and enhances its transcriptional activity, contributing to NSCLC malignancy.
  • USP7 inhibition represents a promising therapeutic strategy for NSCLC patients with ETV4 dysregulation or hyperactivated MAPK signaling.
  • Targeting USP7 could disrupt the ETV4-MAPK7-ERK5 axis, thereby inhibiting tumor progression.
Keywords:
ERK5ETV4USP7deubiquitinationnon–small cell lung cancer

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