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BRMS1 contributes to the negative regulation of uPA gene expression through recruitment of HDAC1 to the NF-κB binding site of the uPA promoter

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Abstract

The BRMS1 metastasis suppressor was recently shown to negatively regulate NF-κB signaling and down regulate NF-κB-dependent uPA expression. Here we confirm that BRMS1 expression correlates with reduced NF-κB DNA binding activity in independently derived human melanoma C8161.9 cells stably expressing BRMS1. We show that knockdown of BRMS1 expression in these cells using small interfering RNA (siRNA) leads to the reactivation of NF-κB DNA binding activity and re-expression of uPA. Further, we confirm that BRMS1 expression does not alter IKKβ kinase activity suggesting that BRMS1-dependent uPA regulation does not occur through inhibition of the classical upstream activators of NF-κB. BRMS1 has been implicated as a corepressor of HDAC1 and consistent with this, we show that BRMS1 promotes HDAC1 recruitment to the NF-κB binding site of the uPA promoter and is associated with reduced H3 acetylation. We also confirm that BRMS1 expression stimulates disassociation of p65 from the NF-κB binding site of the uPA promoter consistent with its reduced DNA binding activity. These data suggest that BRMS1 recruits HDAC1 to the NF-κB binding site of the uPA promoter, modulates histone acetylation of p65 on the uPA promoter, leading to reduced NF-κB binding activity on its consensus sequence, and reduced transactivation of uPA expression.

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Acknowledgments

Supported in part from funding from the Lerner Foundation (G.C.) and CARES (G.C.) and NIH grants RO-1 CA100748 (N.S.), P50-CA89019 (D.W).

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Authors and Affiliations

  1. Endocrine Research Unit, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Muzaffer Cicek

  2. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Ryuichi Fukuyama, Steven Sizemore & Nywana Sizemore

  3. Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN, 55905, USA

    Mine S. Cicek

  4. Department of Pathology, The Comprehensive Cancer Center, and the National Foundation for Cancer Research Center for Metastasis Research, University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Danny R. Welch

  5. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Graham Casey

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  1. Muzaffer Cicek
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  2. Ryuichi Fukuyama
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  3. Mine S. Cicek
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  7. Graham Casey
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Correspondence to Graham Casey.

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Cicek, M., Fukuyama, R., Cicek, M.S. et al. BRMS1 contributes to the negative regulation of uPA gene expression through recruitment of HDAC1 to the NF-κB binding site of the uPA promoter. Clin Exp Metastasis 26, 229–237 (2009). https://doi.org/10.1007/s10585-009-9235-1

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