期刊
CANCER LETTERS
卷 385, 期 -, 页码 207-214出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2016.10.021
关键词
Cdc20; SPOP; Degradation; Ubiquitination; Cancer
类别
资金
- National Institute of Health [R01CA177910, R01GM094777]
- National Basic Research Program of China [2015CB943003]
- National Natural Science Foundation of China [81370753]
- China Scholarship Council (CSC) [201506100054]
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. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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