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

Endocrinology. 2001 Sep;142(9):3817-27. doi: 10.1210/endo.142.9.8380.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence / genetics
  • Breast Neoplasms / genetics*
  • Butyrates / pharmacology*
  • Cell Line
  • DNA-Binding Proteins / physiology*
  • Female
  • Histone Deacetylase Inhibitors*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Insulin-Like Growth Factor Binding Protein 3 / genetics*
  • Molecular Sequence Data
  • Promoter Regions, Genetic / drug effects*
  • Promoter Regions, Genetic / physiology*
  • Response Elements / physiology
  • Sp1 Transcription Factor / physiology*
  • Sp3 Transcription Factor
  • Transcription Factors / physiology*


  • Butyrates
  • DNA-Binding Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Insulin-Like Growth Factor Binding Protein 3
  • SP3 protein, human
  • Sp1 Transcription Factor
  • Transcription Factors
  • Sp3 Transcription Factor
  • trichostatin A