title: Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis.
abstract: Hemorrhagic cystitis is an inflammatory and ulcerative bladder condition associated with systemic chemotherapeutics, like cyclophosphomide. Earlier, we reported reactive oxygen species resulting from cyclophosphamide metabolite, acrolein, causes global methylation followed by silencing of DNA damage repair genes. Ogg1 (8-oxoguanine DNA glycosylase) is one such silenced base excision repair enzyme that can restore DNA integrity. The accumulation of DNA damage results in subsequent inflammation associated with pyroptotic death of bladder smooth muscle cells. We hypothesized that reversing inflammasome-induced imprinting in the bladder smooth muscle could prevent the inflammatory phenotype. Elevated recruitment of Dnmt1 and Dnmt3b to the Ogg1 promoter in acrolein treated bladder muscle cells was validated by the pattern of CpG methylation revealed by bisulfite sequencing. Knockout of Ogg1 in detrusor cells resulted in accumulation of reactive oxygen mediated 8-Oxo-dG and spontaneous pyroptotic signaling. Histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), restored Ogg1 expression in cells treated with acrolein and mice treated with cyclophosphamide superior to the standard of care, mesna or nicotinamide-induced DNA demethylation. SAHA restored cyclophosphamide-induced bladder pathology to that of untreated control mice. The observed epigenetic imprinting induced by inflammation suggests a new therapeutic target for the treatment of hemorrhagic cystitis.
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Subhash
authors.initials: S
authors.lastname: Haldar
authors.affiliation: Division of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Dru
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Mishra
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Tripathi
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Greater Los Angeles Veterans Administration, Los Angeles, CA, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Duong
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Greater Los Angeles Veterans Administration, Los Angeles, CA, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Angara
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Greater Los Angeles Veterans Administration, Los Angeles, CA, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandez
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
authors.affiliation: Department of Medicine, Samuel Ochin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Greater Los Angeles Veterans Administration, Los Angeles, CA, USA.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Bhowmick
mesh_terms: D000171:Acrolein / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D003520:Cyclophosphamide / Q000633:toxicity*; D003556:Cystitis / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015080:Mesna / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000077337:Vorinostat; D000097584:DNA Methyltransferase 3B
chemical_list: D000171:Acrolein; D003520:Cyclophosphamide; D004248:DNA (Cytosine-5-)-Methyltransferases; D045647:DNA Glycosylases; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015080:Mesna; D009536:Niacinamide; D017382:Reactive Oxygen Species; D000077337:Vorinostat; D000097584:DNA Methyltransferase 3B; C485990:Ogg1 protein, mouse