Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis

Subhash Haldar, Christopher Dru, Rajeev Mishra, Manish Tripathi, Frank Duong, Bryan Angara, Ana Fernandez, Moshe Arditi, Neil A. Bhowmick

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number39257
JournalScientific Reports
Volume6
DOIs
StatePublished - Dec 20 2016
Externally publishedYes

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Histone Deacetylase Inhibitors
Cystitis
DNA Repair
DNA Damage
Urinary Bladder
Acrolein
Cyclophosphamide
Methylation
Mesna
Inflammasomes
DNA Glycosylases
Inflammation
Niacinamide
DNA
Standard of Care
Epigenomics
Muscle Cells
Smooth Muscle Myocytes
Smooth Muscle
Reactive Oxygen Species

All Science Journal Classification (ASJC) codes

  • General

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Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. / Haldar, Subhash; Dru, Christopher; Mishra, Rajeev; Tripathi, Manish; Duong, Frank; Angara, Bryan; Fernandez, Ana; Arditi, Moshe; Bhowmick, Neil A.

In: Scientific Reports, Vol. 6, 39257, 20.12.2016.

Research output: Contribution to journalArticle

Haldar, S, Dru, C, Mishra, R, Tripathi, M, Duong, F, Angara, B, Fernandez, A, Arditi, M & Bhowmick, NA 2016, 'Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis', Scientific Reports, vol. 6, 39257. https://doi.org/10.1038/srep39257
Haldar, Subhash ; Dru, Christopher ; Mishra, Rajeev ; Tripathi, Manish ; Duong, Frank ; Angara, Bryan ; Fernandez, Ana ; Arditi, Moshe ; Bhowmick, Neil A. / Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. In: Scientific Reports. 2016 ; Vol. 6.
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