Abstract
The loss of transforming growth factor-beta (TGF-beta) response due to the dysregulation of TGF-beta receptors type I (RI) and type II (RII) is well known for its contribution to oncogenesis. Estrogen receptor-expressing breast cancer cells are refractory to TGF-beta-mediated growth control because of the reduced expression of TGF-beta receptors. Although RII is required for the binding of TGF-beta to RI, RI is responsible for directly transducing TGF-beta signals through the Smad protein family. Treatment of estrogen receptor-expressing MCF-7L and ZR75 breast cancer cells with the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) led to a dramatic induction of RI. Accumulation of acetylated histones H3 and H4 was observed in the SAHA-treated cells. Chromatin immunoprecipitation analysis followed by PCR with RI promoter-specific primers indicated an accumulation of acetylated histones in chromatin associated with the RI gene, suggesting that histone deacetylation was involved in the transcriptional inactivation of RI. SAHA treatment stimulated RI promoter activity through the inhibition of Sp1/Sp3-associated HDAC activity. Histone acetyltransferase p300 stimulated RI promoter activity, thus further confirming the involvement of HDAC activity in the transcriptional repression of RI. Significantly, SAHA-mediated RI regeneration restored the TGF-beta response in breast cancer cells.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Acetylation
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Acetyltransferases / metabolism
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Activin Receptors, Type I / chemistry
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Activin Receptors, Type I / metabolism*
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Blotting, Western
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Chromatin / metabolism
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DNA Methylation
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DNA-Binding Proteins / metabolism
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Genes, Reporter
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Histone Acetyltransferases
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Histone Deacetylases / metabolism*
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Histones / metabolism
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Humans
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Hydroxamic Acids / pharmacology
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Luciferases / metabolism
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Precipitin Tests
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Promoter Regions, Genetic
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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Sp1 Transcription Factor / metabolism
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Sp3 Transcription Factor
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Time Factors
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Transcription Factors / metabolism
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Transcription, Genetic
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Transfection
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Transforming Growth Factor beta / metabolism*
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Vorinostat
Substances
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Chromatin
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DNA-Binding Proteins
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Histones
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Hydroxamic Acids
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Receptors, Transforming Growth Factor beta
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SP3 protein, human
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Sp1 Transcription Factor
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Transcription Factors
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Transforming Growth Factor beta
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Sp3 Transcription Factor
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Vorinostat
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Luciferases
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Acetyltransferases
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Histone Acetyltransferases
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Protein Serine-Threonine Kinases
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Activin Receptors, Type I
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Receptor, Transforming Growth Factor-beta Type I
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Histone Deacetylases