DNAR-05. A ROLE FOR TAZ/YAP IN DNA DAMAGE REPAIR IN GLIOBLASTOMA
نویسندگان
چکیده
Abstract Previous studies have shown that glioma stem-like cells (GSCs) evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying biology therapy resistance GSCs is required. Our group has TAZ, a transcriptional co-factor highly expressed in about 70% glioblastomas (GBMs). TAZ its paralog YAP are oncogenic drivers brain tumor progression. overexpressing undergo proneural (PN) to mesenchymal (MS) subtype transition, which accompanied by aggressive phenotypes such increased grade treatment GSC xenografts. Although functions TAZ/YAP well established, exact mediated cell fate transition GBM not fully understood. Here, we present novel functional interaction between DNA-dependent protein kinase (DNA-PK) response exposure ionizing radiation GSCs. Mass-spectrometric analyses TAZ-binding proteins showed DNA-PK complex composed catalytic subunit (DNA-PKcs) Ku heterodimer Ku70 K80 interacted with TAZ. Immunoprecipitation both well. Interaction YAP/TAZ TEAD was enhanced radiation. DNA-PKcs phosphorylated phosphorylation level these were after irradiation, consistent an proteins. Intriguingly, siRNA knockdown resulted inactivation DNA-PKcs, although stability affected. Pharmacological inhibition TAZ/YAPTEAD DNA damage suppressed proliferation, this effect synergized irradiation. We conclude integral components pharmacological targeting TAZ/YAP/TEAD pathway can overcome
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2022
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noac209.337