Prostate cancer. Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Science. 2014 Oct 3;346(6205):85-89. doi: 10.1126/science.1250255. Epub 2014 Oct 2.

Abstract

Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants. We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Binding Sites / genetics
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / metabolism
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Invasiveness
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Oncogene Proteins / metabolism
  • Poly-ADP-Ribose Binding Proteins
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Repressor Proteins / genetics*
  • Repressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination / genetics*

Substances

  • Carrier Proteins
  • Chromosomal Proteins, Non-Histone
  • Dek protein, human
  • Nuclear Proteins
  • Oncogene Proteins
  • Poly-ADP-Ribose Binding Proteins
  • Repressor Proteins
  • SPOP protein, human
  • TRIM24 protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex