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Molecular and Cellular Biology, December 2006, p. 8683-8696, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00940-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Breast Cancer Metastasis Suppressor 1 Functions as a Corepressor by Enhancing Histone Deacetylase 1-Mediated Deacetylation of RelA/p65 and Promoting Apoptosis{triangledown} ,{dagger}

Yuan Liu, Philip W. Smith, and David R. Jones*

Department of Surgery, University of Virginia School of Medicine, Charlottesville, Virginia

Received 26 May 2006/ Returned for modification 1 August 2006/ Accepted 11 September 2006

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.

* Corresponding author. Mailing address: Department of Surgery, Box 800679, University of Virginia, Charlottesville, VA 22908-0679. Phone: (434) 243-6443. Fax: (434) 982-1026. E-mail: djones{at}virginia.edu.

{triangledown} Published ahead of print on 25 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, December 2006, p. 8683-8696, Vol. 26, No. 23
0270-7306/06/$08.00+0     doi:10.1128/MCB.00940-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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