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Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation

Jian An1, Shancheng Ren2, Stephen J Murphy3

  • 1Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Molecular Cell
|September 8, 2015
PubMed

Insights

Prostate cancer involves SPOP mutations and TMPRSS2-ERG rearrangements. This study shows SPOP normally degrades ERG protein, but mutations or ERG truncation prevent this, driving cancer growth and suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • SPOP mutations and TMPRSS2-ERG rearrangements are common in prostate cancer.
  • The functional relationship between SPOP and ERG in prostate cancer is not well understood.

Purpose of the Study:

  • To investigate the functional interplay between SPOP and ERG in prostate cancer.
  • To elucidate the mechanism by which SPOP regulates ERG protein levels.

Main Methods:

  • Investigated SPOP's role as an E3 ubiquitin ligase.
  • Analyzed SPOP-mediated ubiquitination and proteasome degradation of wild-type ERG.
  • Examined the impact of SPOP mutations and TMPRSS2-ERG fusions on ERG degradation.

Main Results:

  • SPOP targets wild-type ERG for degradation via ubiquitination.
  • Prostate cancer-associated SPOP mutations impair ERG degradation.
  • TMPRSS2-ERG fusions produce truncated ERG resistant to SPOP-mediated degradation.

Conclusions:

  • Degradation resistance of truncated ERG is a novel mechanism contributing to its elevation in prostate cancer.
  • Targeting ERG resistance to SPOP degradation offers a potential therapeutic strategy for specific prostate cancer subtypes.

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