Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly
Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly
复制标题
前列腺癌相关的 SPOP 突变通过上调 Caprin1 依赖性应激颗粒组装来增强癌细胞存活和多西紫杉醇耐药性
DOI：
10.1186/s12943-019-1096-x
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发表时间：
2019-11-26
期刊：
影响因子：
37.3
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Shi, Qing;Zhu, Yasheng;Wang, Chenji
背景编码E3泛素连接酶底物结合接头SPOP的基因在前列腺癌中经常发生突变，但SPOP突变在前列腺癌发病机制中的作用尚不清楚。应激颗粒(SG)组装是一种进化上保守的应激状态下细胞存活的策略，在人类癌症中经常上调。我们研究了前列腺癌中SG基因突变在SG异常激活中的作用，并探讨了其在耐药中的作用机制。方法采用酵母双杂交方法鉴定SG核蛋白CAPRIN1为SPOP相互作用蛋白。在细胞系、患者样本和异种移植模型中进行了一系列的功能分析，以探讨SPOP调节前列腺癌SG信号的生物学意义和临床相关性。结果胞浆形式的野生型(WT)SPOP识别并触发泛素依赖的CAPRIN1降解。在表达SPOP突变的前列腺癌细胞系和患者样本中，CAPRIN1丰度升高。SPOP WT抑制SG组装，而前列腺癌相关突变体以CAPRIN1依赖的方式增强SG组装。SPOP基因敲除或表达前列腺癌相关的SPOP突变体可使前列腺癌细胞对SG诱导剂(如多西紫杉醇、亚砷酸钠和过氧化氢)诱导的死亡产生抵抗。结论在SPOP突变的前列腺癌中，SG组装异常升高。在前列腺癌中，SPOP突变引起对化疗药物如多西紫杉醇诱导的细胞应激的抵抗。
BackgroundThe gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. Stress granules (SG) assembly is an evolutionarily conserved strategy for survival of cells under stress, and often upregulated in human cancers. We investigated the role of SPOP mutations in aberrant activation of the SG in prostate cancer and explored the relevanve of the mechanism in therapy resistance.MethodsWe identified SG nucleating protein Caprin1 as a SPOP interactor by using the yeast two hybrid methods. A series of functional analyses in cell lines, patient samples, and xenograft models were performed to investigate the biological significance and clinical relevance of SPOP regulation of SG signaling in prostate cancer.ResultsThe cytoplasmic form of wild-type (WT) SPOP recognizes and triggers ubiquitin-dependent degradation of Caprin1. Caprin1 abundance is elevated in SPOP-mutant expressing prostate cancer cell lines and patient specimens. SPOP WT suppresses SG assembly, while the prostate cancer-associated mutants enhance SG assembly in a Caprin1-dependent manner. Knockout of SPOP or expression of prostate cancer-associated SPOP mutants conferred resistance to death caused by SG inducers (e.g. docetaxel, sodium arsenite and H2O2) in prostate cancer cells.ConclusionsSG assembly is aberrantly elevated in SPOP-mutated prostate cancer. SPOP mutations cause resistance to cellular stress induced by chemtherapeutic drug such as docetaxel in prostate cancer.