BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis

• Verfasst von: Valinciute, Gintvile [VerfasserIn]
• Verfasst von: Veldwijk, Marlon Romano [VerfasserIn]
• Verfasst von: Herskind, Carsten [VerfasserIn]
• Verfasst von: Wenz, Frederik [VerfasserIn]
• Titel: BET-bromodomain inhibitors modulate epigenetic patterns at the diacylglycerol kinase alpha enhancer associated with radiation-induced fibrosis
• Mitwirkende: Plass, Christoph
• Mitwirkende: Schmezer, Peter
• Mitwirkende: Popanda, Odilia
• Verf.angabe: Gintvile Valinciute, Christoph Weigel, Marlon R. Veldwijk, Christopher C. Oakes, Carsten Herskind, Frederik Wenz, Christoph Plass, Peter Schmezer, Odilia Popanda
• E-Jahr: 2017
• Jahr: 12 September 2017
• Umfang: 7 S.
• Fussnoten: Gesehen am 28.08.2018 ; Available online 12 September 2017
• Titel Quelle: Enthalten in: Radiotherapy and oncology
• Ort Quelle: Amsterdam [u.a.] : Elsevier Science, 1983
• Jahr Quelle: 2017
• Band/Heft Quelle: 125(2017), 1, Seite 168-174
• ISSN Quelle: 1879-0887
• DOI: doi:10.1016/j.radonc.2017.08.028
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Bromodomain inhibitor JQ1
• Sach-SW: DGKA
• Sach-SW: Enhancer
• Sach-SW: Epigenetics
• Sach-SW: Radiation-induced fibrosis
• K10plus-PPN: 1580466591

Abstract

Background and purpose: Fibrosis is a frequent adverse effect of radiotherapy and no effective treatments are currently available to prevent or reverse fibrotic disease. We have previously identified altered epigenetic patterns at a gene enhancer of the diacylglycerol kinase alpha (DGKA) locus in normal skin fibroblasts derived from fibrosis patients. An open chromatin pattern related to radiation-inducibility of DGKA is associated with onset of radiation-induced fibrosis. Here, we explore epigenetic modulation of DGKA as a way to mitigate predisposition to fibrosis. Material and methods: We studied the effect of the BET-bromodomain inhibitors (JQ1, PFI-1) on DGKA inducibility in primary fibroblasts. Hence, DGKA transcription was additionally induced by the radiomimetic drug bleomycin, and DGKA mRNA expression, histone H3K27 acetylation and downstream markers of profibrotic fibroblast activation after BET-bromodomain inhibition were determined. Results: BET-bromodomain inhibition suppressed induction of DGKA in bleomycin-treated fibroblasts, reduced H3K27ac at the DGKA enhancer and repressed collagen marker gene expression. Alterations in fibroblast morphology and reduction of collagen deposition were observed. Conclusion: For the DGKA enhancer, we show that BET-bromodomain inhibitors can alter the epigenetic landscape of fibroblasts, thus counteracting profibrotic transcriptional events. Interference with epigenetic patterns of fibrosis predisposition may provide novel preventive therapies that improve radiotherapy.