title: Sulforaphane modulates telomerase activity via epigenetic regulation in prostate cancer cell lines.
abstract: Epidemiologic studies have revealed that diets rich in sulforaphane (SFN), an isothiocyanate present in cruciferous vegetables, are associated with a marked decrease in prostate cancer incidence. The chemo-preventive role of SFN is associated with its histone de-acetylase inhibitor activity. However, the effect of SFN on chromatin composition and dynamic folding, especially in relation to HDAC inhibitor activity, remains poorly understood. In this study, we found that SFN can inhibit the expression and activity of human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase, in 2 prostate cancer cell lines. This decrease in gene expression is correlated with SFN-induced changes in chromatin structure and composition. The SFN-mediated changes in levels of histone post-translational modifications, more specifically acetylation of histone H3 lysine 18 and di-methylation of histone H3 lysine 4, 2 modifications linked with high risk of prostate cancer recurrence, were associated with regulatory elements within the hTERT promoter region. Chromatin condensation may also play a role in SFN-mediated hTERT repression, since expression and recruitment of MeCP2, a known chromatin compactor, were altered in SFN treated prostate cancer cells. Chromatin immuno-precipitation (ChIP) of MeCP2 showed enrichment over regions of the hTERT promoter with increased nucleosome density. These combined results strongly support a role for SFN in the mediation of epigenetic events leading to the repression of hTERT in prostate cancer cells. This ability of SFN to modify chromatin composition and structure associated with target gene expression provides a new model by which dietary phytochemicals may exert their chemoprevention activity.
authors.affiliation: a Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.|b Cell Differentiation and Development Center, Marshall University, Huntington, WV, USA.
authors.forename: Ata
authors.initials: A
authors.lastname: Abbas
authors.affiliation: a Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.|b Cell Differentiation and Development Center, Marshall University, Huntington, WV, USA.|c Department of Biochemistry and Microbiology, Marshall University School of Medicine, Huntington, WV, USA.
authors.forename: J Adam
authors.initials: JA
authors.lastname: Hall
authors.affiliation: a Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.|b Cell Differentiation and Development Center, Marshall University, Huntington, WV, USA.|c Department of Biochemistry and Microbiology, Marshall University School of Medicine, Huntington, WV, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Patterson
authors.affiliation: d Oregon State University, School of Biological and Population Health Sciences, Linus Pauling Institute, Corvallis, OR, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Ho
authors.affiliation: d Oregon State University, School of Biological and Population Health Sciences, Linus Pauling Institute, Corvallis, OR, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Hsu
authors.affiliation: e Kuwait University, Health Sciences Center, Faculty of Medicine, Molecular Pathology Unit, Kuwait City, Kuwait.
authors.forename: Fahd
authors.initials: F
authors.lastname: Al-Mulla
authors.affiliation: a Department of Biological Sciences, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, USA.|b Cell Differentiation and Development Center, Marshall University, Huntington, WV, USA.|c Department of Biochemistry and Microbiology, Marshall University School of Medicine, Huntington, WV, USA.
authors.forename: Philippe T
authors.initials: PT
authors.lastname: Georgel
mesh_terms: D000107:Acetylation; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry*; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D008239:Lysine / Q000378:metabolism; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000378:metabolism*; D008745:Methylation; D009707:Nucleosomes / Q000378:metabolism; D064209:Phytochemicals / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000201:enzymology*; D011499:Protein Processing, Post-Translational; D013454:Sulfoxides; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017879:Isothiocyanates; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D009707:Nucleosomes; D064209:Phytochemicals; D013454:Sulfoxides; C509186:TERT protein, human; D019098:Telomerase; C016766:sulforaphane; D008239:Lysine
keywords: HDAC; cancer de la prostate; chromatin; chromatine; histone post-translational modifications; modifications post-traductionnelles d’histones; prostate cancer; sulforaphane; telomerase; télomérase