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J. Biol. Chem., Vol. 282, Issue 49, 35457-35470, December 7, 2007

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Histone Deacetylase 3 Down-regulates Cholesterol Synthesis through Repression of Lanosterol Synthase Gene Expression^*

Alejandro Villagra, Natalia Ulloa, Xiaohong Zhang, Zhigang Yuan, Eduardo Sotomayor, and Edward Seto¹

From the H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612 and the Department of Clinical Biochemistry and Immunology, School of Pharmacy, University of Concepcion, Concepcion Chile

In vertebrates, a key step in the biosynthesis of cholesterol and steroid hormones is the conversion of (S)-2,3-oxidosqualene to lanosterol. The enzyme that catalyzes this complex cyclization/rearrangement step via the protosteryl cation intermediate is lanosterol synthase ((S)-2,3-epoxysqualene mutase (cyclizing, lanosterol forming), EC 5.4.99.7 [EC] ). Because of the crucial role that lanosterol synthase plays in cholesterol biosynthesis, there is great interest in the identification of drugs that target this enzyme for anticholesteremic purposes. Although most studies on lanosterol synthase in the past have focused on the structural and biochemical functions of this enzyme, almost nothing is known concerning how the synthesis of lanosterol synthase is regulated. Here, we report that histone deacetylase 3 (HDAC3) represses transcription from the lanosterol synthase promoter. Overexpression of HDAC3 decreases, whereas knockdown of HDAC3 by small interfering RNA increases, endogenous lanosterol synthase mRNA in cells. Similarly, in transient transfection assays, overexpression of HDAC3 decreases, whereas depletion of HDAC3 increases, expression of a reporter gene under the control of the lanosterol synthase promoter. Stable cell lines that overexpress HDAC3 show a decrease in lanosterol synthase mRNA and have lower cholesterol concentrations compared with parental cells. Extensive promoter analyses coupled with chromatin immunoprecipitation assays reveal that the transcription factor YY1 binds to and recruits HDAC3 to the lanosterol synthase promoter. Together, our results demonstrate that HDAC3 represses the synthesis of a key regulatory enzyme and reveal a novel mechanism by which the cholesterol biosynthetic pathway can be regulated.

Received for publication, February 27, 2007 , and in revised form, October 4, 2007.

^* This work was supported by American Heart Association Grant 0755298B, National Institutes of Health Grant CA109699, and a grant from the Kaul Foundation (to E. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental table.

¹ To whom correspondence should be addressed: H. Lee Moffitt Cancer Center and Research Institute, SRB 23011, 12902 Magnolia Dr., Tampa, FL 33612. Tel.: 813-745-6754; Fax: 813-745-4907; E-mail: ed.seto{at}moffitt.org.

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