Restoration of transforming growth factor-β signaling through receptor RI induction by histone deacetylase activity inhibition in breast cancer cells

Sudhakar Ammanamanchi, Michael G. Brattain

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

The loss of transforming growth factor-β (TGF-β) response due to the dysregulation of TGF-β 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-β-mediated growth control because of the reduced expression of TGF-β receptors. Although RII is required for the binding of TGF-β to RI, RI is responsible for directly transducing TGF-β 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-β response in breast cancer cells.

Original languageEnglish (US)
Pages (from-to)32620-32625
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number31
DOIs
StatePublished - Jul 30 2004

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Histone Deacetylases
Transforming Growth Factors
Restoration
Cells
Breast Neoplasms
Histones
Growth Factor Receptors
Estrogen Receptors
Chromatin
Smad Proteins
Histone Acetyltransferases
Histone Deacetylase Inhibitors
Chromatin Immunoprecipitation
Refractory materials
Regeneration
Carcinogenesis
Genes
Polymerase Chain Reaction
vorinostat
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Restoration of transforming growth factor-β signaling through receptor RI induction by histone deacetylase activity inhibition in breast cancer cells. / Ammanamanchi, Sudhakar; Brattain, Michael G.

In: Journal of Biological Chemistry, Vol. 279, No. 31, 30.07.2004, p. 32620-32625.

Research output: Contribution to journalArticle

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