DNAR-03. A ROLE FOR THE INTERACTION BETWEEN DNA-DEPENDENT PROTEIN KINASE (DNA-PK) AND TAZ IN INDUCING GLIOMA STEM-LIKE CELL (GSC) RADIO-RESISTANCE

Abstract

Abstract Glioblastoma (GBM) is a primary brain tumor that is virtually incurable. Previous studies have shown that glioma stem-like cells (GSCs) are a particularly resistant subpopulation of GBM. Thus, a greater understanding of the mechanisms underlying therapy resistance in GSCs is required. TAZ is a transcriptional cofactor highly expressed in about 70% of GBMs. TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. Our group has shown that GSCs overexpressing TAZ undergo a proneural to mesenchymal subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. However, the molecular mechanisms of TAZ-mediated cell fate transition and GBM treatment resistance remain elusive. Previously, our group identified a novel interaction between DNA-dependent protein kinase (DNA-PK) and TAZ in response to exposure to ionizing radiation (IR) in GSCs. Here, we extend our previous findings by contextualizing the significance of this novel interaction in altering sensitivity to IR in GSCs. We demonstrate that prolonged culture of GSCs treated with etoposide increases TAZ expression. Furthermore, si-RNA knockdown of TAZ increases the number of γH2AX foci post-IR. Intriguingly, knocking down both TAZ/YAP does not increase the number of γH2AX foci post-IR in comparison to single knockdown of TAZ. Additionally, DNA-PK inhibitor treatment in GSCs reduces the half-life of TAZ. In contrast, GSCs treated with IR increases the half-life of TAZ compared to mock-irradiated cells. A combination of IR and DNA-PK inhibitor treatment in GSCs reduces the half-life of TAZ compared to GSCs treated with IR and DMSO, implicating the role of the recruitment of TAZ to DNA damage breaks and its resulting interactions with DNA-PK to induce radio-resistance. Overall, this study reports how interaction of DNA-PK with TAZ globally induces a GSC radio-resistant phenotype, highlighting the potential role of TAZ as a therapeutic target for GBM.