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| Home > Publications database > Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced pro-fibrotic fibroblast responses. |
| Home > Publications database > Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced pro-fibrotic fibroblast responses. |
| Journal Article | DKFZ-2022-00409 |
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2022
Wiley-Liss
Bognor Regis
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Please use a persistent id in citations: doi:10.1002/ijc.33989
Abstract: 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.
Keyword(s): BET ; fibroblast activation ; radiation ; selective bromodomain inhibitors
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