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

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 bee...

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Hauptverfasser: Liu, Chun-Shan (VerfasserIn) , Rioja, Inmaculada (VerfasserIn) , Bakr, Ali (VerfasserIn) , Veldwijk, Marlon Romano (VerfasserIn) , Sperk, Elena (VerfasserIn) , Herskind, Carsten (VerfasserIn) , Weichenhan, Dieter (VerfasserIn) , Prinjha, Rab K. (VerfasserIn) , Plass, Christoph (VerfasserIn) , Schmezer, Peter (VerfasserIn) , Popanda, Odilia (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 15 July 2022
In: International journal of cancer
Year: 2022, Jahrgang: 151, Heft: 2, Pages: 275-286
ISSN:1097-0215
DOI:10.1002/ijc.33989
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1002/ijc.33989
Verlag, kostenfrei, Volltext: http://onlinelibrary.wiley.com/doi/abs/10.1002/ijc.33989
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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.
Beschreibung:Online veröffentlicht: 3. März 2022
Gesehen am 05.12.2023
Beschreibung:Online Resource
ISSN:1097-0215
DOI:10.1002/ijc.33989

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