Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1 Leslie G. Wooten-Blanks 1 , Pengfei Song 1 , Can E. Senkal and Besim Ogretmen 2 The Department of Biochemistry and Molecular Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA 2 Correspondence: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA. E-mail: ogretmen@musc.edu In this study, distinct roles of de novo -generated endogenous ceramides and mechanisms by which deacetylated Sp3 regulates the hTERT promoter activity in response to ceramide signaling were explored. The generation of C 18 -ceramide via the expression of ceramide synthase 1 (CerS1), and not C 16 -ceramide by CerS5 or CerS6 expression, resulted in repression of the hTERT promoter via deacetylation of Sp3 by histone deacetylase 1 (HDAC1) in A549 human lung adenocarcinoma cells. Then roles and mechanisms of action of ceramide-mediated deacetylation of Sp3 in inhibiting the hTERT promoter were determined using constitutively deacetylated or acetylated Sp3 mutants at lysine (K) 551. Expression of the deacetylated Sp3 mutant resulted in repression, whereas its acetylated mutant induced basal hTERT promoter activity in Drosophila S2 cells, which do not express any endogenous Sp3, and in A549 cells. Remarkably, chromatin immunoprecipitation data revealed that acetylated Sp3 mutant (K551Q-Sp3) did not bind whereas deacetylated Sp3 (K551R-Sp3) mutant bound strongly to the promoter DNA, resulting in the recruitment of histone deacetylase 1 (HDAC1) and inhibition of the association of RNA polymerase II with the promoter. Mechanistically, increased generation of C 18 -ceramide by hCerS1 expression, but not by its catalytically inactive mutant, mediated the association and recruitment of the deacetylated Sp3/HDAC1 complex to the hTERT promoter DNA, resulting in the local histone H3 deacetylation and repression of the promoter.—Wooten-Blanks, L. G., Song, P., Senkal, C. E., Ogretmen, B. Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1. Key Words: longevity assurance gene 1 (LASS1) • ceramide synthase • de novo ceramide generation • sphingolipids • lung cancer
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Mechanisms of ceramide-mediated repression of the human telomerase reverse transcriptase promoter via deacetylation of Sp3 by histone deacetylase 1
Wooten-Blanks, Leslie G.; Song, Pengfei; Senkal, Can E.; Ogretmen, Besim
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, Volume 21 (12): 3386
Fed of American Socs for Experimental Biology – Oct 1, 2007
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