title: Prostate cancer-associated mutation in SPOP impairs its ability to target Cdc20 for poly-ubiquitination and degradation.
abstract: 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.
authors: Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Fei
authors: F
authors: Wu
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Xiangpeng
authors: X
authors: Dai
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Wenjian
authors: W
authors: Gan
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Lixin
authors: L
authors: Wan
authors: Departments of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Min
authors: M
authors: Li
authors: Departments of Medicine, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Nicholas
authors: N
authors: Mitsiades
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors: Wenyi
authors: W
authors: Wei
authors: Department of Urology, Huashan Hospital, Fudan University, Shanghai 200040, PR China. Electronic address: dr_dingqiang@hotmail.com.
authors: Qiang
authors: Q
authors: Ding
authors: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: jzhang17@bidmc.harvard.edu.
authors: Jinfang
authors: J
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D064199:Cdc20 Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D044842:Cullin Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology; D003959:Diamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D011743:Pyrimidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination
chemical_list: D000970:Antineoplastic Agents; C503645:CUL3 protein, human; D002219:Carbamates; D064199:Cdc20 Proteins; C100318:Cullin 1; D044842:Cullin Proteins; D003517:Cyclopentanes; D003959:Diamines; D004791:Enzyme Inhibitors; D009687:Nuclear Proteins; D011743:Pyrimidines; D012097:Repressor Proteins; C509761:SPOP protein, human; C000593255:apcin; C577488:CDC20 protein, human; C539933:pevonedistat
keywords: Cancer; Cdc20; Degradation; SPOP; Ubiquitination