title: The impact of cruciferous vegetable isothiocyanates on histone acetylation and histone phosphorylation in bladder cancer.
abstract: Cruciferous vegetable intake is associated with reduced risk of bladder cancer, yet mechanisms remain unclear. Cruciferous vegetable isothiocyanates (ITCs), namely sulforaphane (SFN) and erucin (ECN), significantly inhibit histone deacetylase (HDAC) activity in human bladder cancer cells representing superficial to invasive biology (59-83% inhibition with 20μM, 48h treatment), and in bladder cancer xenografts (59±3% ECN inhibition). Individual HDACs inhibited by SFN and ECN include HDACs 1, 2, 4 and 6. Interestingly, global acetylation status of histones H3 or H4 remain unaltered. The interplay between HDAC inhibition and modest modulation of AcH3 and AcH4 status is partially explained by decreased histone acetyl transferase activity (48.8±5.3%). In contrast, a significant decrease in phosphorylation status of all isoforms of histone H1 was observed, concomitant with increased phosphatase PP1β and PP2A activity. Together, these findings suggest that ITCs modulate histone status via HDAC inhibition and phosphatase enhancement. This allows for reduced levels of histone H1 phosphorylation, a marker correlated with human bladder cancer progression. Therefore, ITC-mediated inhibition of histone H1 phosphorylation presents a novel direction of research in elucidating epidemiological relationships and supports future food-based prevention strategies.
  
  
  
  Collectively, our findings suggest that the cruciferous vegetable isothiocyanates: sulforaphane (SFN) and erucin (ECN), impact histones status in bladder cancer cells by modulating specific HDACs and HATs, and enhancing phosphatase activity, resulting in reduction of histone H1 phosphorylation. These findings are significant due to the fact that our previous work positively correlated histone H1 phosphorylation with bladder cancer carcinogenesis and progression. Therefore, we propose that SFN and ECN may inhibit bladder carcinogenesis via epigenetic modulation of gene expression associated with histone H1 phosphorylation. These efforts may elucidate biomarkers useful in epidemiologic studies related to cruciferous vegetable intake and cancer risk or provide intermediate biomarkers for food-based clinical intervention studies in high-risk cohorts.
authors.affiliation: The Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Besma
authors.initials: B
authors.lastname: Abbaoui
authors.affiliation: Department of Chemistry, College of Arts and Sciences, The Ohio State University, Columbus, OH 43210, USA; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Kelly H
authors.initials: KH
authors.lastname: Telu
authors.affiliation: The Integrated Biomedical Science Graduate Program, College of Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Lucas
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Thomas-Ahner
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Food Science and Technology, College of Food, Agricultural, and Environmental Sciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Schwartz
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Division of Medical Oncology, Department of Internal Medicine, College of Medicine; The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Department of Molecular Virology, Immunology and Medical Genetics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA. Electronic address: freitas.5@osu.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Freitas
authors.affiliation: Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA; Division of Medical Oncology, Department of Internal Medicine, College of Medicine; The Ohio State University, Columbus, OH 43210, USA. Electronic address: amir.mortazavi@osumc.edu.
authors.forename: Amir
authors.initials: A
authors.lastname: Mortazavi
mesh_terms: D000107:Acetylation; D000818:Animals; D001937:Brassica / Q000737:chemistry*; D045744:Cell Line, Tumor; D064593:Heterografts; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology*; D051379:Mice; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D013440:Sulfides / Q000494:pharmacology; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000178:diet therapy / Q000188:drug therapy* / Q000517:prevention & control; D014675:Vegetables / Q000737:chemistry
chemical_list: D006657:Histones; D017879:Isothiocyanates; D013440:Sulfides; D013454:Sulfoxides; D013861:Thiocyanates; C073539:erucin; C016766:sulforaphane
keywords: Bladder cancer; Broccoli; Cruciferous vegetables; Erucin; Histone acetylation; Histone phosphorylation; Isothiocyanates; Sulforaphane