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J. Biol. Chem., Vol. 280, Issue 11, 10047-10054, March 18, 2005

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Trichostatin A Induces Transforming Growth Factor Type II Receptor Promoter Activity and Acetylation of Sp1 by Recruitment of PCAF/p300 to a Sp1·NF-Y Complex^*

Weiqi Huang, Shujie Zhao, Sudhakar Ammanamanchi, Michael Brattain, Kolaparthi Venkatasubbarao, and James W. Freeman¶||**

From the Department of Medicine, Division of Medical Oncology and ^||Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, and ^¶Research and Development, Audie Murphy Veterans Administration Hospital, San Antonio, Texas 78229

Transforming growth factor type II receptor (TRII) is a tumor suppressor gene that can be transcriptionally silenced by histone deacetylases (HDACs) in cancer cells. In this report, we demonstrated the mechanism by which trichostatin A (TSA), an inhibitor of HDAC, induces the expression of TRII in human pancreatic cancer cell lines by modulating the transcriptional components that bind a specific DNA region of the TRII promoter. This region of the TRII promoter possesses Sp1 and NF-Y binding sites in close proximity (located at –102 and –83, respectively). Treatment of cells with TSA activates the TRII promoter in a time-dependent manner through the recruitment of p300 and PCAF into a Sp1·NF-Y·HDAC complex that binds this DNA element. The recruitment of p300 and PCAF into the complex is associated with a concomitant acetylation of Sp1 and an overall decrease in the amount of HDAC associated with the complex. Transient overexpression of p300 or PCAF potentiated TSA-induced TRII promoter activity. The effect of PCAF was dependent on its histone acetyltransferase activity, whereas that of p300 was independent. Stable transfection of PCAF caused an increase in TRII mRNA expression, the association of PCAF with TRII promoter, and the acetylation of Sp1. Taken together, these results showed that TSA treatment of pancreatic cancer cells leads to transcriptional activation of the TRII promoter through modulation of the components of a Sp1·NF-Y·p300·PCAF·HDAC-1 multiprotein complex. Moreover, the interaction of NF-Y with the Sp1-associated complex may further explain why this specific Sp1 site mediates transcriptional responsiveness to TSA.

Received for publication, July 30, 2004 , and in revised form, December 21, 2004.

^* This work was supported by National Institutes of Health Grant CA96122 (to J. W. F.). 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 should be addressed: Dept. of Medicine, Division of Medical Oncology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-5298; Fax: 210-567-6687; E-mail: freemanjw{at}uthscsa.edu.

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