Histone deacetylase 3 down-regulates cholesterol synthesis through repression of lanosterol synthase gene expression.
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). 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.
Villagra
Alejandro
A
H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Ulloa
Natalia
N
Zhang
Xiaohong
X
Yuan
Zhigang
Z
Sotomayor
Eduardo
E
Seto
Edward
E
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D003412:Cricetulus; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D019751:Intramolecular Transferases / Q000096:biosynthesis*; D007810:Lanosterol / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013185:Squalene / Q000031:analogs & derivatives / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D050986:YY1 Transcription Factor / Q000378:metabolism; D000099186:Histone Deacetylase 3
D002784:Cholesterol; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D019751:Intramolecular Transferases; D007810:Lanosterol; D034741:RNA, Small Interfering; D013185:Squalene; D050986:YY1 Transcription Factor; D000099186:Histone Deacetylase 3; C494698:YY1 protein, human; C520393:oxidosqualene; C021924:lanosterol synthase