Abstract
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.
Highlights
The gene encoding the E3 ubiquitin ligase substrate-binding adaptor Speckle type BTB/POZ protein (SPOP) is frequently mutated in primary prostate cancer, but how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood
Identification of Caprin1 as a novel SPOP interactor By performing a yeast two-hybrid screen in a human fetal brain cDNA library using full length SPOP as bait, we identified 32 clones corresponded to Caprin1 protein
We explored whether Caprin1 is an authentic SPOP substrate, and whether its physiological function is dysregulated in SPOP-mutated prostate cancer
Summary
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. Recurrent mutations in the SPOP gene occur in up to 15% of primary prostate cancers [1,2,3,4]. The vast majority of prostate cancer-associated SPOP mutations identified so far affect evolutionarily conserved residues in the MATH domain, suggesting that these mutations may alter the interaction between SPOP and its substrates [3]. SPOP mutations lead to increased prostate cancer cell proliferation, invasion and immune escape in vivo, implying that SPOP mutations are driving molecular events in prostate cancer initiation and progression [10, 11, 16]. Limited numbers of SPOP substrates have been identified and functionally explored
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