This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Walker, G. E. Articles by Oh, Y. Search for Related Content PubMed PubMed Citation Articles by Walker, G. E. Articles by Oh, Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Breast Cancer

Butyrate, a Histone Deacetylase Inhibitor, Activates the Human IGF Binding Protein-3 Promoter in Breast Cancer Cells: Molecular Mechanism Involves an Sp1/Sp3 Multiprotein Complex

Department of Pediatrics (G.E.W., E.M.W., Y.O.), Oregon Health Sciences University, Portland, Oregon 97201; and Baylor College of Medicine (D.P.), Houston, Texas 77030

Address all correspondence and requests for reprints to: Youngman Oh, Ph.D., Department of Pediatrics, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201. E-mail: ohy{at}ohsu.edu

Specific cell growth stimulators and inhibitors regulate IGF binding protein-3 (IGFBP-3), where in turn IGFBP-3 mediates their biological effects. The molecular mechanism(s) by which these factors regulate IGFBP-3 are unknown. Sodium butyrate, a histone deacetylase inhibitor causing growth arrest and differentiation, increases IGFBP-3 expression. We investigated the molecular mechanism of this induction using an IGFBP-3 promoter reporter system in MCF-7 and Hs578T breast cancer cells. IGFBP-3 promoter activity was induced up to 40-fold following a 24-h treatment with sodium butyrate and 46-fold in cells treated with trichostatin A, a pure histone deacetylase inhibitor. Deletion analysis of the IGFBP-3 promoter identified key sodium butyrate-responsive element(s) to a 45-bp region containing consensus binding sites for Sp1 and activating protein-2. Sp1 binding to the Sp1 site and Sp3 to the activating protein-2/GA-box played a functional role in sodium butyrate’s activation of the IGFBP-3 promoter, however, with no change in binding direct sodium butyrate regulation was attributed to cofactors. The histone acetyltransferase p300 and histone deacetylase-1 were identified in multiprotein complexes containing DNA bound Sp1 and Sp3, with p300 accumulating following sodium butyrate treatment. Taken together, these data suggest that sodium butyrate increases IGFBP-3 expression by activating the IGFBP-3 promoter via an Sp1/Sp3 multiprotein complex, a mechanism that may be important for other key regulators of IGFBP-3.