SPOP mutation drives prostate neoplasia without stabilizing oncogenic transcription factor ERG

J Clin Invest. 2018 Jan 2;128(1):381-386. doi: 10.1172/JCI96551. Epub 2017 Dec 4.


Nearly 50% of prostate cancers harbor gene fusions that lead to overexpression of the transcription factor ERG, while a mutually exclusive 10% of prostate cancers harbor recurrent mutations in the gene encoding the E3 ubiquitin ligase SPOP. Recent reports suggest that SPOP acts as a ubiquitin ligase for ERG and propose that ERG stabilization is the oncogenic effector of SPOP mutation. Here, we used human prostate cancer samples and showed that the vast majority of human SPOP-mutant cancers do not express ERG. Comparison of SPOP-mutant and ERG-fusion organoid models showed evidence of divergent, rather than common, transcriptional programs. Furthermore, expression of prostate cancer-associated SPOP mutations in genetically engineered mouse models of SPOP-mutant prostate cancer did not result in the expression of ERG protein in histologically normal prostate glands, high-grade prostatic intraepithelial neoplasia, invasive adenocarcinoma, or prostate organoids. In summary, we found no evidence that ERG is an effector of SPOP mutation in human prostate cancer or mouse models.

Keywords: Oncogenes; Oncology.

Publication types

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

MeSH terms

  • Animals
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism*
  • Neoplasms, Experimental / pathology
  • Nuclear Proteins / genetics
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism*
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Stability
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • Repressor Proteins / metabolism*
  • Transcriptional Regulator ERG / genetics
  • Transcriptional Regulator ERG / metabolism*
  • Ubiquitin-Protein Ligase Complexes


  • ERG protein, human
  • ERG protein, mouse
  • Nuclear Proteins
  • Oncogene Proteins
  • Repressor Proteins
  • SPOP protein, human
  • Transcriptional Regulator ERG
  • Spop protein, mouse
  • Ubiquitin-Protein Ligase Complexes