SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

Mol Cell. 2015 Sep 17;59(6):917-30. doi: 10.1016/j.molcel.2015.07.026. Epub 2015 Sep 3.


The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Cell Line, Tumor
  • Cell Movement
  • Cullin Proteins / metabolism
  • Disease Progression
  • Etoposide / pharmacology
  • HEK293 Cells
  • Humans
  • Male
  • Molecular Sequence Data
  • Neoplasm Invasiveness
  • Nuclear Proteins / physiology*
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Interaction Domains and Motifs
  • Proteolysis
  • Repressor Proteins / physiology*
  • Trans-Activators / metabolism*
  • Transcriptional Regulator ERG
  • Tumor Suppressor Proteins / physiology
  • Ubiquitination*


  • Antineoplastic Agents, Phytogenic
  • CUL3 protein, human
  • Cullin Proteins
  • ERG protein, human
  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Tumor Suppressor Proteins
  • Etoposide