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.
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.
Mesh Terms:
Base Sequence, Breast Neoplasms, Butyrates, Cell Line, DNA-Binding Proteins, Female, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Insulin-Like Growth Factor Binding Protein 3, Molecular Sequence Data, Promoter Regions, Genetic, Response Elements, Sp1 Transcription Factor, Sp3 Transcription Factor, Transcription Factors
Base Sequence, Breast Neoplasms, Butyrates, Cell Line, DNA-Binding Proteins, Female, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Insulin-Like Growth Factor Binding Protein 3, Molecular Sequence Data, Promoter Regions, Genetic, Response Elements, Sp1 Transcription Factor, Sp3 Transcription Factor, Transcription Factors
Endocrinology
Date: Sep. 01, 2001
PubMed ID: 11517158
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