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Mutated SPOP E3 Ligase Promotes 17βHSD4 Protein Degradation to Drive Androgenesis and Prostate Cancer Progression

Lei Shi1,2, Yuqian Yan2, Yundong He2

  • 1Department of Radiation Oncology, the Fourth Hospital of Harbin Medical University, Harbin, China.

Cancer Research
|March 25, 2021
PubMed

Insights

Speckle-type poxvirus and zinc finger domain protein (SPOP) regulates 17βHSD4 stability, impacting prostate cancer growth. SPOP mutations disrupt this, increasing testosterone and cancer progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer progression is linked to intratumoral androgenesis and aberrant androgen receptor (AR) activation.
  • The precise molecular mechanisms governing these processes are not fully understood.

Purpose of the Study:

  • To elucidate the role of speckle-type poxvirus and zinc finger domain protein (SPOP) in regulating 17βHSD4 stability and its impact on prostate cancer.
  • To investigate the interplay between SPOP, SGK3, SKP2, and 17βHSD4 in the context of prostate cancer.

Main Methods:

  • Investigated SPOP-17βHSD4 interactions and ubiquitination.
  • Analyzed the role of SGK3-mediated phosphorylation and SKP2 in 17βHSD4 degradation.
  • Utilized prostate cancer cell cultures and mouse models to assess the functional consequences of SPOP mutations and SKP2 overexpression.

Main Results:

  • Ectopic SPOP expression stabilizes 17βHSD4 by promoting nondegradable polyubiquitination.
  • SGK3-mediated phosphorylation antagonizes SPOP's effect, leading to SKP2-dependent degradation of 17βHSD4.
  • Prostate cancer-associated SPOP mutations impair 17βHSD4 interaction, leading to its degradation, increased testosterone production, and enhanced prostate cancer cell growth.

Conclusions:

  • SPOP and SKP2 oppositely regulate 17βHSD4 degradation and intratumoral androgenesis in prostate cancer.
  • SPOP mutations or SKP2 overexpression contribute to prostate cancer progression by reducing 17βHSD4 levels and increasing androgen synthesis.
  • This study reveals a novel mechanism for aberrant AR activation in SPOP-mutated prostate cancer and identifies potential biomarkers for AR-targeted therapies.

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