Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer

被引:18
作者
Gao, Kun [1 ]
Shi, Qing [2 ,3 ]
Liu, Yajuan [2 ,3 ]
Wang, Chenji [2 ,3 ]
机构
[1] Tongji Univ, Sch Med, Shanghai Matern & Infant Hosp 1, Dept Clin Lab, Shanghai, Peoples R China
[2] Fudan Univ, Shanghai Engn Res Ctr Ind Microorganisms, Sch Life Sci,Shanghai Stomatol Hosp, Moe Engn Res Ctr Gene Technol,State Key Lab Genet, Shanghai 200438, Bejining, Peoples R China
[3] Fudan Univ, Shanghai Engn Res Ctr Ind Microorganisms, Sch Life Sci,Sch Stomatol, Moe Engn Res Ctr Gene Technol,State Key Lab Genet, Shanghai 200438, Bejining, Peoples R China
基金
上海市自然科学基金; 中国国家自然科学基金;
关键词
Gene mutation; KEAP1; oxidative stress; phase separation; prostate cancer; SPOP; SQSTM1; ubiquitination;
D O I
10.1080/15548627.2022.2062873
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2013 / 2015
页数:3
相关论文
共 1 条
[1]   SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer [J].
Shi, Qing ;
Jin, Xiaofeng ;
Zhang, Pingzhao ;
Li, Qian ;
Lv, Zeheng ;
Ding, Yan ;
He, Huiying ;
Wang, Yijun ;
He, Yuanlong ;
Zhao, Xiaying ;
Zhao, Shi-Min ;
Li, Yao ;
Gao, Kun ;
Wang, Chenji .
CELL DEATH AND DIFFERENTIATION, 2022, 29 (06) :1228-1239