Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 26, Issue 23, Pages 8683-8696Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00940-06
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Funding
- NHLBI NIH HHS [T32 HL007849, T32 HL 007849] Funding Source: Medline
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The antiapoptotic transcription factor NF-kappa B 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-kappa B-regulated antiapoptotic gene products. BRMS1 immunoprecipitates with the RelA/p65 subunit of NF-kappa B 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-kappa B-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-kappa B.
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