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Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer
Kun Gao1, Qing Shi2, Yajuan Liu2
1Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.
Abstract:
SQSTM1/p62 is a selective macroautophagy/autophagy receptor that drives ubiquitinated cargos toward the lysosome for degradation, and also a stress-induced scaffold protein that helps cells to cope with oxidative stress through sequestrating KEAP1 and subsequent activation of the NFE2L2/NRF2 antioxidant pathway. Accumulating evidence implicates SQSTM1 dysregulation in the induction of multiple oncogenic transformations in vivo. SPOP (speckle type BTB/POZ protein), an E3 ubiquitin ligase adaptor, is the most frequently mutated gene in prostate cancer (Pca), but the molecular mechanisms underlying how SPOP mutations contribute to PCa tumorigenesis are still largely unknown. In a recent study, we describe a new role for SPOP as a negative regulator of autophagy and NFE2L2 pathway activation. SPOP binds and induces the non-degradative ubiquitination of SQSTM1 at Lys420. This post-translational modification decreases SQSTM1 body formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing SQSTM1-dependent autophagy, KEAP1 sequestration, and NFE2L2 activation. Notably, PCa-associated SPOP mutants lose the capacity to ubiquitinate SQSTM1 and instead enhance autophagy and the antioxidant response in a dominant-negative manner. Thus, our findings indicate the critical roles of autophagy and NFE2L2 pathway activation in PCa tumorigenesis by oncogenic SPOP mutations.
Insights
Speckle type BTB/POZ protein (SPOP) regulates autophagy and antioxidant pathways by modifying SQSTM1/p62. Prostate cancer-associated SPOP mutations disrupt this regulation, promoting tumorigenesis.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- SQSTM1/p62 acts as an autophagy receptor and a scaffold protein regulating oxidative stress response via the KEAP1-NFE2L2/NRF2 pathway.
- Dysregulation of SQSTM1 is implicated in various cancers.
- SPOP is frequently mutated in prostate cancer, but its role in tumorigenesis is unclear.
Purpose of the Study:
- To investigate the role of SPOP in regulating autophagy and the NFE2L2/NRF2 antioxidant pathway.
- To elucidate the molecular mechanisms by which SPOP mutations contribute to prostate cancer.
Main Methods:
- Investigated SPOP's interaction with SQSTM1/p62.
- Analyzed the ubiquitination status of SQSTM1/p62 by SPOP.
- Assessed the impact of SPOP modification on autophagy and NFE2L2/NRF2 pathway activation.
- Utilized prostate cancer-associated SPOP mutants.
Main Results:
- SPOP binds SQSTM1/p62 and induces its non-degradative ubiquitination at Lys420.
- This ubiquitination suppresses SQSTM1/p62 body formation, condensation, dimerization, and ubiquitin-binding capacity.
- SPOP negatively regulates autophagy, KEAP1 sequestration, and NFE2L2/NRF2 activation.
- Prostate cancer-associated SPOP mutants fail to ubiquitinate SQSTM1/p62 and enhance autophagy and antioxidant responses in a dominant-negative manner.
Conclusions:
- SPOP acts as a negative regulator of autophagy and the NFE2L2/NRF2 pathway through SQSTM1/p62 ubiquitination.
- Oncogenic SPOP mutations in prostate cancer lead to enhanced autophagy and antioxidant responses, contributing to tumorigenesis.
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