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| Home > Publications database > Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced pro-fibrotic fibroblast responses. > print |
| 001 | 179027 | ||
| 005 | 20241220120849.0 | ||
| 024 | 7 | _ | |a 10.1002/ijc.33989 |2 doi |
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| 037 | _ | _ | |a DKFZ-2022-00409 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Liu, Chun-Shan |0 P:(DE-He78)32d60018ed55b6e3b2b3f6b839380357 |b 0 |e First author |
| 245 | _ | _ | |a Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced pro-fibrotic fibroblast responses. |
| 260 | _ | _ | |a Bognor Regis |c 2022 |b Wiley-Liss |
| 336 | 7 | _ | |a article |2 DRIVER |
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| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1653902708_3384 |2 PUB:(DE-HGF) |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a #EA:B370#EA:F240#LA:B370# / 151(2):275-286 |
| 520 | _ | _ | |a Radiotherapy 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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| 650 | _ | 7 | |a BET |2 Other |
| 650 | _ | 7 | |a fibroblast activation |2 Other |
| 650 | _ | 7 | |a radiation |2 Other |
| 650 | _ | 7 | |a selective bromodomain inhibitors |2 Other |
| 700 | 1 | _ | |a Rioja, Inmaculada |b 1 |
| 700 | 1 | _ | |a Bakr, Ali Mohyeldin Ali |0 P:(DE-He78)277add45f831355e9453b41e651f6411 |b 2 |
| 700 | 1 | _ | |a Veldwijk, Marlon R |b 3 |
| 700 | 1 | _ | |a Sperk, Elena |b 4 |
| 700 | 1 | _ | |a Herskind, Carsten |b 5 |
| 700 | 1 | _ | |a Weichenhan, Dieter |0 P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f |b 6 |
| 700 | 1 | _ | |a Prinjha, Rab K |b 7 |
| 700 | 1 | _ | |a Plass, Christoph |0 P:(DE-He78)4301875630bc997edf491c694ae1f8a9 |b 8 |
| 700 | 1 | _ | |a Schmezer, Peter |0 P:(DE-He78)141ce740f5d881812d2675147b72ecaf |b 9 |
| 700 | 1 | _ | |a Popanda, Odilia |0 P:(DE-He78)37610ef78c733753f0836ce0e41b9fda |b 10 |e Last author |
| 773 | _ | _ | |a 10.1002/ijc.33989 |g p. ijc.33989 |0 PERI:(DE-600)1474822-8 |n 2 |p 275-286 |t International journal of cancer |v 151 |y 2022 |x 0020-7136 |
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