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USP7 promotes chemotherapy resistance and DNA damage response through stabilizing and deubiquitinating KDM4A in

Hailang Yang1, Xiaoqiang Liu1, Jianqiang Nie2

  • 1Jiangxi Provincial Key Laboratory of Urinary System Diseases, Department of Urology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.

Cell Death & Disease
|December 22, 2025
PubMed

Insights

Overexpression of KDM4A is linked to poor bladder cancer prognosis. Targeting the USP7-KDM4A interaction sensitizes bladder cancer to cisplatin treatment by increasing DNA damage.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Bladder cancer is a prevalent malignancy.
  • Cisplatin resistance in advanced bladder cancer presents a significant therapeutic hurdle.

Purpose of the Study:

  • To identify novel molecular targets that regulate cisplatin sensitivity in bladder cancer.
  • To investigate the role of KDM4A and its interacting partners in bladder cancer progression and chemoresistance.

Main Methods:

  • Analysis of KDM4A expression in clinical bladder cancer cohorts.
  • In vitro cell culture and in vivo animal models.
  • Co-immunoprecipitation and mass spectrometry to identify protein interactions.
  • Functional assays to validate the role of the USP7-KDM4A axis.

Main Results:

  • KDM4A overexpression correlates with poor prognosis and promotes proliferation in bladder cancer.
  • USP7 was identified as a KDM4A-interacting protein, deubiquitinating KDM4A and preventing its degradation.
  • A positive correlation between USP7 and KDM4A expression was observed in clinical samples.
  • Inhibition of the USP7-KDM4A axis enhanced cisplatin-induced DNA damage and improved treatment sensitivity.

Conclusions:

  • The USP7-KDM4A axis is a critical driver of bladder cancer cell proliferation and chemoresistance.
  • Targeting the USP7-KDM4A interaction represents a promising strategy to overcome cisplatin resistance in bladder cancer.

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