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.

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

“…Bisulfite sequencing. Bisulfite sequencing was performed as described previously (58). Briefly, genomic DNA was extracted from rection for the multiplicity problem.…”

Mutual inhibition between HDAC9 and miR-17 regulates osteogenesis of human periodontal ligament stem cells in inflammatory conditions

“…HDAC controls gene expression by enzymatic removal of the negatively charged acetyl groups from the positively charged lysine on histone tails, resulting in tightening the negatively charged DNA backbone and preventing its access for transcription. Previous studies reported that HDACs can be activated in response to persistent inflammatory signals during pneumonia, rheumatoid arthritis, hemorrhagic cystitis, and other diseases, driving the balance toward inflammation rather than resolution 4 – 6 .…”

Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance

“…Immunodetection. Paraffin-embedded tissue was processed for immunohistochemical localization was performed with antibodies against p-AKT, p-TAK, p-histoneH3 (Cell Signaling), C3 (Santa Cruz Biotechnology), and TUNEL (Thermo Fisher Scientific) as previously described before (58,59). All of the slides were scanned using Leica SCN400 (Leica Micro System) and analyzed by Tissue IA Optimizer (Leica).…”