BRMS1 Suppresses Lung Cancer Metastases Through an E3 Ligase Function on Histone Acetyltransferase p300

Cancer Res. 2013 Feb 15;73(4):1308-17. doi: 10.1158/0008-5472.CAN-12-2489. Epub 2012 Dec 26.

Abstract

The mechanisms through which the metastasis suppressor gene BRMS1 functions are poorly understood. Herein, we report the identification of a previously undescribed E3 ligase function of BRMS1 on the histone acetyltransferase p300. BRMS1 induces polyubiquitination of p300, resulting in its proteasome-mediated degradation. We identify BRMS1 as the first eukaryote structural mimic of the bacterial IpaH E3 ligase family and establish that the evolutionarily conserved CXD motif located in BRMS1 is responsible for its E3 ligase function. Mutation of this E3 ligase motif not only abolishes BRMS1-induced p300 polyubiquitination and degradation, but importantly, dramatically reduces the metastasis suppressor function of BRMS1 in both in vitro and in vivo models of lung cancer metastasis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Line, Tumor
  • E1A-Associated p300 Protein / genetics
  • E1A-Associated p300 Protein / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Metastasis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms, Experimental / genetics
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • RNA Interference
  • Repressor Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • Transplantation, Heterologous
  • Tumor Burden / genetics
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • BRMS1 protein, human
  • Neoplasm Proteins
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Ubiquitin-Protein Ligases