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J. Biol. Chem., Vol. 279, Issue 31, 32620-32625, July 30, 2004

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Restoration of Transforming Growth Factor- Signaling through Receptor RI Induction by Histone Deacetylase Activity Inhibition in Breast Cancer Cells^*

Sudhakar Ammanamanchi and Michael G. Brattain

From the Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263

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

Received for publication, March 9, 2004 , and in revised form, April 29, 2004.

^* This work was supported by National Institutes of Health Grants CA 38173, CA 72001, and CA 16056. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-1574; Fax: 716-845-8857; E-mail: sudhakar.ammanamanchi{at}roswellpark.org.

To whom correspondence may be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-3044; Fax: 716-845-4437; E-mail: michael.brattain{at}roswellpark.org.

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