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Updated: Oct 7, 2025

Quantitative Analysis of Autophagy using Advanced 3D Fluorescence Microscopy
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SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer

Qing Shi1,2, Xiaofeng Jin3, Pingzhao Zhang4

  • 1State Key Laboratory of Genetic Engineering, MOE Engineering Research Center of Gene Technology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, 200438, China.

Cell Death and Differentiation
|January 6, 2022
PubMed

Insights

SPOP protein regulates autophagy and oxidative stress response by modifying p62. SPOP mutations in prostate cancer disrupt this, promoting tumor growth via increased autophagy and Nrf2 activity.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • p62/SQSTM1 is a crucial autophagy receptor and stress-response scaffold protein implicated in neurodegenerative diseases and cancer.
  • Mutations in SPOP, an E3 ubiquitin ligase adapter, are common in prostate cancer (PCa), but their role in tumorigenesis is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which SPOP mutations contribute to prostate cancer development.
  • To investigate the interaction between SPOP, p62, and the Nrf2 pathway in PCa.

Main Methods:

  • Investigated the ubiquitination of p62 by SPOP in vitro and in cellulo.
  • Assessed the impact of SPOP-mediated p62 ubiquitination on p62 function, autophagy, and Nrf2 pathway activation.
  • Analyzed the function of PCa-associated SPOP mutants.

Main Results:

  • Cytoplasmic SPOP induces non-degradative ubiquitination of p62, suppressing autophagy and Nrf2-mediated antioxidant gene expression.
  • PCa-associated SPOP mutants fail to ubiquitinate p62, leading to enhanced autophagy and redox response.
  • SPOP mutations promote PCa tumorigenesis by dysregulating p62-mediated autophagy and Nrf2 signaling.

Conclusions:

  • SPOP acts as a negative regulator of p62-dependent autophagy and Nrf2 activation.
  • Dysfunctional SPOP in PCa promotes oncogenesis through enhanced autophagy and redox signaling.
  • Targeting autophagy and Nrf2 pathways may offer therapeutic strategies for SPOP-mutated prostate cancer.

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