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

Fei Wu1, Xiangpeng Dai2, Wenjian Gan2

  • 1Department 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.

Cancer Letters
|November 5, 2016
PubMed

Insights

Speckle-type POZ protein (SPOP) regulates prostate cancer by degrading the Cdc20 oncoprotein. Mutations in SPOP impair this process, leading to elevated Cdc20 and resistance to treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Mutations in Speckle-type POZ protein (SPOP) are found in up to 15% of prostate cancer patients.
  • The precise role of SPOP in prostate cancer development is not fully understood.

Purpose of the Study:

  • To investigate the physiological function of SPOP in prostate tumorigenesis.
  • To identify novel SPOP-interacting proteins and their role in cancer progression.

Main Methods:

  • Identified Cdc20 as a novel ubiquitin substrate of SPOP.
  • Investigated the interaction between SPOP, Cullin 3, and Cdc20 using co-immunoprecipitation.
  • Assessed the effect of SPOP mutations on Cdc20 degradation.
  • Utilized pharmacological inhibitors (MLN4924) and genetic depletion (Cullin 3 knockdown) to study protein stability.

Main Results:

  • SPOP directly interacts with the oncoprotein Cdc20, promoting its poly-ubiquitination and degradation.
  • Cullin 3, an E3 ligase adaptor, is crucial for SPOP-mediated Cdc20 degradation.
  • Prostate cancer-associated SPOP mutants lose the ability to interact with and degrade Cdc20.
  • SPOP-deficient prostate cancer cells exhibit increased Cdc20 levels and resistance to Cdc20 inhibitors.

Conclusions:

  • SPOP plays a critical role in prostate tumorigenesis by targeting the Cdc20 oncoprotein for degradation.
  • Dysregulation of the SPOP-Cdc20 axis contributes to prostate cancer development and treatment resistance.
Keywords:
CancerCdc20DegradationSPOPUbiquitination

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