Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer
Enhanced autophagy and NFE2L2/NRF2 pathway activation in SPOP mutation-driven prostate cancer
复制标题
SPOP 突变驱动的前列腺癌中自噬增强和 NFE2L2/NRF2 通路激活
DOI：
10.1080/15548627.2022.2062873
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发表时间：
2022-04-21
期刊：
影响因子：
13.3
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Gao, Kun;Shi, Qing;Wang, Chenji
摘要SQSTM 1/p62是一种选择性自噬受体，可将泛素化的物质推向溶酶体降解，同时也是一种应激诱导的支架蛋白，通过螯合KEAP 1和随后激活NFE 2L 2/NRF 2抗氧化途径来帮助细胞科普氧化应激。越来越多的证据表明SQSTM 1在体内诱导多种致癌转化中的失调。SPOP（speckle type BTB/POZ protein，斑点型BTB/POZ蛋白）是一种E3泛素连接酶接头，是前列腺癌（Pca）中最常发生突变的基因，但SPOP突变如何导致Pca肿瘤发生的分子机制仍不清楚。在最近的一项研究中，我们描述了SPOP作为自噬和NFE 2L 2通路激活的负调节剂的新作用。SPOP结合并诱导SQSTM 1在Lys 420处的非降解性泛素化。这种翻译后修饰减少了SQSTM 1体形成、液相凝聚、二聚化和泛素结合能力，从而抑制SQSTM 1依赖性自噬、KEAP 1隔离和NFE 2L 2激活。值得注意的是，PCa相关的SPOP突变体失去了泛素化SQSTM 1的能力，而是以显性负性方式增强自噬和抗氧化反应。因此，我们的研究结果表明，自噬和NFE 2L 2通路激活在致癌SPOP突变的PCa肿瘤发生中的关键作用。
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.