Related Experiment Video

Updated: Jun 8, 2025

Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel
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Generation of Prostate Cancer Cell Models of Resistance to the Anti-mitotic Agent Docetaxel

Published on: September 8, 2017

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USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in

Sheng Li1,2, Situ Xiong1,2, Zhongqi Li1,2

  • 1Department of Urology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, China.

Cell Death & Disease
|November 5, 2024
PubMed

Insights

The deubiquitinating enzyme USP3 stabilizes SMARCA5, promoting DNA repair and chemotherapy resistance in prostate cancer. Targeting the USP3-SMARCA5 axis may improve treatment for resistant cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • SMARCA5 is crucial for DNA repair and its dysfunction causes neurodevelopmental disorders.
  • The regulation of SMARCA5 in prostate cancer (PCa) is not well understood.
  • Understanding SMARCA5 regulation is vital for developing new PCa therapies.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating SMARCA5 stability in prostate cancer.
  • To investigate the role of USP3 in SMARCA5 regulation and its impact on chemotherapy resistance.
  • To explore the therapeutic potential of targeting the USP3-SMARCA5 axis in prostate cancer.

Main Methods:

  • Investigated the interaction between USP3 and SMARCA5 using biochemical assays.
  • Assessed the effect of USP3 on SMARCA5 ubiquitination and stability.
  • Utilized in vitro and in vivo models to evaluate the role of USP3 and SMARCA5 in docetaxel resistance.
  • Analyzed clinical prostate cancer tissues to correlate USP3 and SMARCA5 expression.

Main Results:

  • USP3 directly interacts with SMARCA5 and removes its K63-linked polyubiquitination, enhancing SMARCA5 stability.
  • Depletion of USP3 or SMARCA5 increased sensitivity of PCa cells to docetaxel.
  • Overexpression of USP3 conferred docetaxel resistance in SMARCA5-silenced cells.
  • USP3 is upregulated in PCa tissues and positively correlates with SMARCA5 expression.

Conclusions:

  • USP3 stabilizes SMARCA5, promoting DNA double-strand break (DSB) repair and docetaxel resistance in prostate cancer.
  • The USP3-SMARCA5 axis is a key regulator of DNA repair and chemotherapy response.
  • Targeting the USP3-SMARCA5 axis presents a promising therapeutic strategy for chemotherapy-resistant prostate cancer.

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