NUP98-p65 complex regulates DNA repair to maintain glioblastoma stem cells.

in FASEB journal : official publication of the Federation of American Societies for Experimental Biology by Feifei Li, Ying Zhang, Jiahui Li, Ranran Jiang, Shusheng Ci

TLDR

  • The study identifies NUP98-p65 complex as a novel node in the regulation of DNA repair, suggesting a potential therapeutic strategy for glioblastoma patients.

Abstract

The nuclear pore complex (NPC) is an evolutionarily conserved structure that maintains the traffic between the nucleus and cytoplasm. Here, we profiled the expression of nucleoporins (NUPs) in glioblastoma stem cells (GSCs) and found that NUP98 promoted GSC maintenance and therapeutic resistance. GSCs preferentially expressed NUP98, which is essential for GSC tumorigenesis in vitro and in vivo. RNA sequencing demonstrated that NUP98 regulated the expression of key DNA damage and repair pathways. NUP98 formed a complex with transcription factor p65 to directly activate genes involved in homologous repair. Attenuation of NUP98 or p65 expression induced unrepaired intrinsic DNA damage and sensitized GSC to ionizing radiation. Clinically, overexpression of NUP98 informs poor clinical outcome among glioblastoma (GBM) patients. Collectively, our results demonstrate that NUP98-p65 represents a novel node in the regulation of DNA repair, suggesting a therapeutic strategy with potential clinical benefits for GBM patients.

Overview

  • The study profiles the expression of nucleoporins (NUPs) in glioblastoma stem cells (GSCs) and found that NUP98 promotes GSC maintenance and therapeutic resistance.
  • GSCs preferentially express NUP98, which is essential for GSC tumorigenesis in vitro and in vivo.
  • The study aims to uncover the significance of NUP98 in glioblastoma tumorigenesis and identify potential therapeutic targets for glioblastoma patients.

Comparative Analysis & Findings

  • RNA sequencing demonstrated that NUP98 regulates the expression of key DNA damage and repair pathways in glioblastoma stem cells.
  • NUP98 forms a complex with transcription factor p65 to directly activate genes involved in homologous repair, promoting glioblastoma stem cell maintenance and therapeutic resistance.
  • Attenuation of NUP98 or p65 expression induces unrepaired intrinsic DNA damage and sensitizes glioblastoma stem cells to ionizing radiation.

Implications and Future Directions

  • The study highlights the potential therapeutic strategy of targeting NUP98-p65 axis to improve disease outcomes for glioblastoma patients.
  • Future studies could investigate the regulatory mechanisms of NUP98-p65 complex and explore their roles in other types of cancer.
  • The overexpression of NUP98 in glioblastoma patients indicates poor clinical outcome, suggesting that NUP98 may serve as a prognostic biomarker.
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