Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis

Mol Cell Biol. 2006 Dec;26(23):8683-96. doi: 10.1128/MCB.00940-06. Epub 2006 Sep 25.


The antiapoptotic transcription factor NF-kappaB is constitutively activated in many cancers and is important for cytokine-mediated progression and metastatic movement of tumors. Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene whose mechanisms of action are poorly understood. In this report, we demonstrate that BRMS1 decreases the transactivation potential of RelA/p65 and ameliorates the expression of NF-kappaB-regulated antiapoptotic gene products. BRMS1 immunoprecipitates with the RelA/p65 subunit of NF-kappaB with protein-protein interactions occurring at the C terminus region of the rel homology domain but not at its known transactivation domains. Moreover, BRMS1 functions as a corepressor by promoting binding of HDAC1 to RelA/p65, where it deacetylates lysine K310 on RelA/p65, which suppresses RelA/p65 transcriptional activity. Selective small interfering RNA knockdown of BRMS1 confirms that chromatin-bound BRMS1 is required for deacetylation of RelA/p65, while enhancing chromatin occupancy of HDAC1 onto the NF-kappaB-regulated promoters cIAP2 and Bfl-1/A1. We observed in cells lacking BRMS1 a dramatic increase in cell viability after the loss of attachment from the extracellular matrix. Collectively, these results suggest that BRMS1 suppresses metastasis through its ability to function as a transcriptional corepressor of antiapoptotic genes regulated by NF-kappaB.

Publication types

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

MeSH terms

  • Acetylation
  • Apoptosis*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line
  • Cell Line, Tumor
  • Cell Survival
  • Chromatin / metabolism
  • Chromatin Immunoprecipitation
  • Escherichia coli / genetics
  • Glutathione Transferase / metabolism
  • Histone Deacetylase 1
  • Histone Deacetylases / metabolism*
  • Humans
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Plasmids / metabolism
  • RNA, Small Interfering
  • Recombinant Fusion Proteins / metabolism
  • Repressor Proteins / metabolism*
  • Transcription Factor RelA / genetics
  • Transcription Factor RelA / metabolism*
  • Transcription, Genetic
  • Transcriptional Activation


  • BRMS1 protein, human
  • Chromatin
  • NF-kappa B
  • Neoplasm Proteins
  • RNA, Small Interfering
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Transcription Factor RelA
  • Glutathione Transferase
  • HDAC1 protein, human
  • Histone Deacetylase 1
  • Histone Deacetylases