Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation.

Recent studies revealed that mutations in SPOP (Speckle-type POZ protein) occur in up to 15% of patients with prostate cancer. However, the physiological role of SPOP in regulating prostate tumorigenesis remains elusive. Here, we identified the Cdc20 oncoprotein as a novel ubiquitin substrate of SPOP. As such, pharmacological inhibition of ...
Cullin-based E3 ligases by MLN4924 could stabilize endogenous Cdc20 in cells. Furthermore, we found that Cullin 3, and, to a less extent, Cullin 1, specifically interacted with Cdc20. Depletion of Cullin 3, but not Cullin 1, could upregulate the abudance of Cdc20 largely via prolonging Cdc20 half-life. Moreover, SPOP, the adaptor protein of Cullin 3 family E3 ligase, specifically interacted with Cdc20, and promoted the poly-ubiquitination and subsequent degradation of Cdc20 in a degron-dependent manner. Importantly, prostate cancer-derived SPOP mutants failed to interact with Cdc20 to promote its degradation. As a result, SPOP-deficient prostate cancer cells with elevated Cdc20 expression became resistant to a pharmacological Cdc20 inhibitor. Therefore, our results revealed a novel role of SPOP in tumorigenesis in part by promoting the degradation of the Cdc20 oncoprotein.
Mesh Terms:
Antineoplastic Agents, Carbamates, Cdc20 Proteins, Cullin Proteins, Cyclopentanes, Diamines, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Enzyme Inhibitors, HeLa Cells, Humans, Male, Molecular Targeted Therapy, Mutation, Nuclear Proteins, Prostatic Neoplasms, Protein Interaction Domains and Motifs, Proteolysis, Pyrimidines, Repressor Proteins, Time Factors, Transfection, Ubiquitination
Cancer Lett.
Date: Dec. 28, 2016
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