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

Mol Cell. 2015 Sep 17;59(6):904-16. doi: 10.1016/j.molcel.2015.07.025. Epub 2015 Sep 3.


SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Cell Proliferation
  • Chromosome Breakpoints
  • HEK293 Cells
  • Humans
  • Male
  • Nuclear Proteins / physiology*
  • Oncogene Proteins, Fusion / physiology*
  • Peptide Fragments / physiology
  • Prostatic Neoplasms / metabolism
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Proteolysis
  • Repressor Proteins / physiology*
  • Trans-Activators / physiology*
  • Transcriptional Regulator ERG
  • Ubiquitination


  • ERG protein, human
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Peptide Fragments
  • Repressor Proteins
  • SPOP protein, human
  • TMPRSS2-ERG fusion protein, human
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Proteasome Endopeptidase Complex