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000179027 1001_ $$0P:(DE-He78)32d60018ed55b6e3b2b3f6b839380357$$aLiu, Chun-Shan$$b0$$eFirst author
000179027 245__ $$aSelective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced pro-fibrotic fibroblast responses.
000179027 260__ $$aBognor Regis$$bWiley-Liss$$c2022
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000179027 500__ $$a#EA:B370#EA:F240#LA:B370# / 151(2):275-286 
000179027 520__ $$aRadiotherapy can induce various adverse effects including fibrosis in cancer patients. Radiation-induced aberrant expression of pro-fibrotic genes has been associated with dysregulated epigenetic mechanisms. Pan-BET (bromodomain and extra-terminal domain) inhibitors, such as JQ1 and I-BET151, have been reported to attenuate the pro-fibrotic response after irradiation. Despite their profound pre-clinical efficacy, the clinical utility of pan-inhibitors is limited due to observed cyto-toxicicities. Recently, inhibitors were developed that selectively target the first (BD1) and second (BD2) bromodomain of the BET proteins (iBET-BD1 (GSK778) and iBET-BD2 (GSK046)). Here, their potential to attenuate radiation-induced fibroblast activation with low-toxicity was investigated. Our results indicated that cell proliferation and cell cycle progression in fibroblasts from BJ cells and six donors were reduced when treated with I-BET151 and iBET-BD1, but not with iBET-BD2. After irradiation, induction of DGKA and pro-fibrotic markers, especially COL1A1 and ACTA2, was attenuated with all BET inhibitors. H3K27ac enrichment was similar at the DGKA enhancer region after I-BET151 treatment and irradiation, but was reduced at the COL1A1 transcription start site and the ACTA2 enhancer site. iBET-BD2 did not change H3K27ac levels in these regions. BRD4 occupancy at these regions was not altered by any of the compounds. Cell migration activity was measured as a characteristic independent of extracellular matrix production and was un-changed in fibroblasts after irradiation and BET inhibitor-treatment. In conclusion, iBET-BD2 efficiently suppressed radiation-induced expression of DGKA and pro-fibrotic markers without showing cyto-toxicity. Thus BD2-selective targeting is a promising new therapeutic avenue for further investigations to prevent or attenuate radiotherapy-induced fibrosis. This article is protected by copyright. All rights reserved.
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000179027 650_7 $$2Other$$aBET
000179027 650_7 $$2Other$$afibroblast activation
000179027 650_7 $$2Other$$aradiation
000179027 650_7 $$2Other$$aselective bromodomain inhibitors
000179027 7001_ $$aRioja, Inmaculada$$b1
000179027 7001_ $$0P:(DE-He78)277add45f831355e9453b41e651f6411$$aBakr, Ali Mohyeldin Ali$$b2
000179027 7001_ $$aVeldwijk, Marlon R$$b3
000179027 7001_ $$aSperk, Elena$$b4
000179027 7001_ $$aHerskind, Carsten$$b5
000179027 7001_ $$0P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f$$aWeichenhan, Dieter$$b6
000179027 7001_ $$aPrinjha, Rab K$$b7
000179027 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b8
000179027 7001_ $$0P:(DE-He78)141ce740f5d881812d2675147b72ecaf$$aSchmezer, Peter$$b9
000179027 7001_ $$0P:(DE-He78)37610ef78c733753f0836ce0e41b9fda$$aPopanda, Odilia$$b10$$eLast author
000179027 773__ $$0PERI:(DE-600)1474822-8$$a10.1002/ijc.33989$$gp. ijc.33989$$n2$$p275-286 $$tInternational journal of cancer$$v151$$x0020-7136$$y2022
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