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


METHODS
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.


RESULTS
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 H2O2) in prostate cancer cells.


CONCLUSIONS
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.
['Shi|Qing|Q|', 'Zhu|Yasheng|Y|', 'Ma|Jian|J|', 'Chang|Kun|K|', 'Ding|Dongling|D|', 'Bai|Yang|Y|', 'Gao|Kun|K|', 'Zhang|Pingzhao|P|', 'Mo|Ren|R|', 'Feng|Kai|K|', 'Zhao|Xiaying|X|', 'Zhang|Liang|L|', 'Sun|Huiru|H|', 'Jiao|Dongyue|D|', 'Chen|Yingji|Y|', 'Sun|Yinghao|Y|', 'Zhao|Shi-Min|SM|', 'Huang|Haojie|H|', 'Li|Yao|Y|', 'Ren|Shancheng|S|', 'Wang|Chenji|C|']
D018797:Cell Cycle Proteins D045744:Cell Line, Tumor D002470:Cell Survival D003594:Cytoplasmic Granules D000077143:Docetaxel D019008:Drug Resistance, Neoplasm D005455:Fluorescent Antibody Technique D006801:Humans D008297:Male D008954:Models, Biological D009154:Mutation D009687:Nuclear Proteins D011471:Prostatic Neoplasms D011485:Protein Binding D059748:Proteolysis D012097:Repressor Proteins D013312:Stress, Physiological D044767:Ubiquitin-Protein Ligases D054875:Ubiquitination
Stress granules Ubiquitination Prostate cancer Gene mutations