Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced profibrotic fibroblast responses

• Verfasst von: Liu, Chun-Shan [VerfasserIn]
• Verfasst von: Rioja, Inmaculada [VerfasserIn]
• Verfasst von: Bakr, Ali [VerfasserIn]
• Verfasst von: Veldwijk, Marlon Romano [VerfasserIn]
• Verfasst von: Sperk, Elena [VerfasserIn]
• Verfasst von: Herskind, Carsten [VerfasserIn]
• Verfasst von: Weichenhan, Dieter [VerfasserIn]
• Verfasst von: Prinjha, Rab K. [VerfasserIn]
• Verfasst von: Plass, Christoph [VerfasserIn]
• Verfasst von: Schmezer, Peter [VerfasserIn]
• Verfasst von: Popanda, Odilia [VerfasserIn]
• Titel: Selective inhibitors of bromodomain BD1 and BD2 of BET proteins modulate radiation-induced profibrotic fibroblast responses
• Titelzusatz: cancer therapy and prevention
• Verf.angabe: Chun-Shan Liu, Inmaculada Rioja, Ali Bakr, Marlon R. Veldwijk, Elena Sperk, Carsten Herskind, Dieter Weichenhan, Rab K. Prinjha, Christoph Plass, Peter Schmezer, Odilia Popanda
• E-Jahr: 2022
• Jahr: 15 July 2022
• Umfang: 12 S.
• Fussnoten: Online veröffentlicht: 3. März 2022 ; Gesehen am 05.12.2023
• Titel Quelle: Enthalten in: International journal of cancer
• Ort Quelle: Bognor Regis : Wiley-Liss, 1966
• Jahr Quelle: 2022
• Band/Heft Quelle: 151(2022), 2, Seite 275-286
• ISSN Quelle: 1097-0215
• DOI: doi:10.1002/ijc.33989
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: BET
• Sach-SW: fibroblast activation
• Sach-SW: radiation
• Sach-SW: selective bromodomain inhibitors
• K10plus-PPN: 1871925592

Abstract

Radiotherapy can induce various adverse effects including fibrosis in cancer patients. Radiation-induced aberrant expression of profibrotic genes has been associated with dysregulated epigenetic mechanisms. Pan-BET (bromodomain and extraterminal domain) inhibitors, such as JQ1 and I-BET151, have been reported to attenuate the profibrotic response after irradiation. Despite their profound preclinical efficacy, the clinical utility of pan-inhibitors is limited due to observed cytotoxicicities. 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 profibrotic 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 unchanged in fibroblasts after irradiation and BET inhibitor-treatment. In conclusion, iBET-BD2 efficiently suppressed radiation-induced expression of DGKA and profibrotic markers without showing cytotoxicity. Thus BD2-selective targeting is a promising new therapeutic avenue for further investigations to prevent or attenuate radiotherapy-induced fibrosis.