title: ATRA transcriptionally induces nSMase2 through CBP/p300-mediated histone acetylation.
abstract: Neutral sphingomyelinase-2 (nSMase2) is a key ceramide-producing enzyme in cellular stress responses. While many posttranslational regulators of nSMase2 are known, emerging evidence suggests a more protracted regulation of nSMase2 at the transcriptional level. Previously, we reported that nSMase2 is induced by all-trans retinoic acid (ATRA) in MCF7 cells and implicated nSMase2 in ATRA-induced growth arrest. Here, we further investigated how ATRA regulates nSMase2. We find that ATRA regulates nSMase2 transcriptionally through the retinoic acid receptor-α, but this is independent of previously identified transcriptional regulators of nSMase2 (Sp1, Sp3, Runx2) and is not through increased promoter activity. Epigenetically, the nSMase2 gene is not repressively methylated in MCF7 cells. However, inhibition of histone deacetylases (HDACs) with trichostatin A (TSA) induced nSMase2 comparably to ATRA; furthermore, combined ATRA and TSA treatment was not additive, suggesting ATRA regulates nSMase2 through direct modulation of histone acetylation. Confirming this, the histone acetyltransferases CREB-binding protein and p300 were required for ATRA induction of nSMase2. Finally, use of class-specific HDAC inhibitors suggested that HDAC4 and/or HDAC5 are negative regulators of nSMase2 expression. Collectively, these results identify a novel pathway of nSMase2 regulation and suggest that physiological or pharmacological modulation of histone acetylation can directly affect nSMase2 levels.
authors.affiliation: Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Clarke
authors.affiliation: Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY.
authors.forename: Achraf A
authors.initials: AA
authors.lastname: Shamseddine
authors.affiliation: Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Jacob
authors.affiliation: Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY.
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Khalife
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Burns
authors.affiliation: Department of Medicine and Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY yusuf.hannun@stonybrookmedicine.edu.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: D000107:Acetylation; D019175:DNA Methylation; D004790:Enzyme Induction; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D061986:MCF-7 Cells; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011499:Protein Processing, Post-Translational; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014212:Tretinoin / Q000502:physiology*; D015854:Up-Regulation; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
chemical_list: D006657:Histones; D006877:Hydroxamic Acids; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; C012589:trichostatin A; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; C491484:SMPD3 protein, human; D013108:Sphingomyelin Phosphodiesterase; D006655:Histone Deacetylases
keywords: all-trans retinoic acid; epigenetic; histone acetyltransferase; histone deacetylase; neutral sphingomyelinase-2; nuclear receptors; retinoids; signal transduction; sphingolipids; transcription