Prostate Cancer-associated SPOP mutations enhance cancer cell survival and docetaxel resistance by upregulating Caprin1-dependent stress granule assembly

• Published in: Molecular cancer 2019-11, Vol.18 (1), p.170-14, Article 170
• Main Authors: Shi, Qing, Zhu, Yasheng, Ma, Jian, Chang, Kun, Ding, Dongling, Bai, Yang, Gao, Kun, Zhang, Pingzhao, Mo, Ren, Feng, Kai, Zhao, Xiaying, Zhang, Liang, Sun, Huiru, Jiao, Dongyue, Chen, Yingji, Sun, Yinghao, Zhao, Shi-Min, Huang, Haojie, Li, Yao, Ren, Shancheng, Wang, Chenji
• Format: Article
• Language: English
• Subjects: Analysis; Antineoplastic agents; Apoptosis; Arsenic compounds; Arsenite; Cancer cells; Cell culture; Cell cycle; Cell Cycle Proteins - metabolism; Cell growth; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Cell Survival - genetics; Cellular stress response; Cloning; Cold; Cytoplasmic Granules - metabolism; Development and progression; DNA methylation; Docetaxel - pharmacology; Drug Resistance, Neoplasm - genetics; Fluorescent Antibody Technique; Gene mutation; Gene mutations; Genetic aspects; Granular materials; Health aspects; Humans; Hydrogen peroxide; Ligases; Male; Models, Biological; Mutants; Mutation; Nuclear Proteins - genetics; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Protein Binding; Proteins; Proteolysis; Repressor Proteins - genetics; Sodium arsenite; Sorafenib; Stress; Stress granules; Stress, Physiological; Survival; Tumor cell lines; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Xenografts; Yeasts
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/s12943-019-1096-x

The 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. We 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. The 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 H O ) in prostate cancer cells. SG 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.