Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis.
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.
Mesh Terms:
Acetylation, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Line, Tumor, Cell Survival, Chromatin, Chromatin Immunoprecipitation, Escherichia coli, Glutathione Transferase, Histone Deacetylase 1, Histone Deacetylases, Humans, NF-kappa B, Neoplasm Proteins, Plasmids, RNA, Small Interfering, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation
Acetylation, Apoptosis, Carcinoma, Non-Small-Cell Lung, Cell Line, Cell Line, Tumor, Cell Survival, Chromatin, Chromatin Immunoprecipitation, Escherichia coli, Glutathione Transferase, Histone Deacetylase 1, Histone Deacetylases, Humans, NF-kappa B, Neoplasm Proteins, Plasmids, RNA, Small Interfering, Recombinant Fusion Proteins, Repressor Proteins, Transcription Factor RelA, Transcription, Genetic, Transcriptional Activation
Mol. Cell. Biol.
Date: Dec. 01, 2006
PubMed ID: 17000776
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