Research ArticleCancer

Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice

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Science Translational Medicine  30 Jun 2021:
Vol. 13, Issue 600, eabc7275
DOI: 10.1126/scitranslmed.abc7275

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SOXing it to glioblastoma

Glioma stem cells promote progression and therapeutic resistance of glioblastoma, a lethal brain tumor. This stemness is maintained by the core transcription factors, including SOX2. Fang et al. now identify DNA-dependent protein kinase (DNA-PK) as crucial for SOX2 stability and maintenance of glioma stem cells. The DNA-PK catalytic subunit phosphorylated SOX2 at S251, preventing its ubiquitination and promoting stemness. Inhibition of DNA-PK with the inhibitor NU7441 led to tumor regression and prolonged survival of tumor-bearing mice and sensitized glioblastoma xenografts to radiotherapy. This suggests that DNA-PK has potential as a therapeutic target for treating glioblastoma.

Abstract

Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially expressed in GSCs compared to matched non–stem cell tumor cells (NSTCs) isolated from patient-derived GBM xenografts. DNA-PKcs phosphorylated human SOX2 at S251, which stabilized SOX2 by preventing WWP2-mediated ubiquitination, thus promoting GSC maintenance. We then demonstrated that when the nuclear DNA of GSCs either in vitro or in GBM xenografts in mice was damaged by irradiation or treatment with etoposide, the DNA-PK complex dissociated from SOX2, which then interacted with WWP2, leading to SOX2 degradation and GSC differentiation. These results suggest that DNA-PKcs–mediated phosphorylation of S251 was critical for SOX2 stabilization and GSC maintenance. Pharmacological inhibition of DNA-PKcs with the DNA-PKcs inhibitor NU7441 reduced GSC tumorsphere formation in vitro and impaired growth of intracranial human GBM xenografts in mice as well as sensitized the GBM xenografts to radiotherapy. Our findings suggest that DNA-PK maintains GSCs in a stem cell state and that DNA damage triggers GSC differentiation through precise regulation of SOX2 stability, highlighting that DNA-PKcs has potential as a therapeutic target in glioblastoma.

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