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FBXO7 Confers Mesenchymal Properties and Chemoresistance in Glioblastoma by Controlling Rbfox2-Mediated Alternative

Shangbiao Li1,2, Yanwen Chen2, Yuxin Xie2

  • 1Department of Radiation Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|October 12, 2023
PubMed

Insights

FBXO7 protein drives mesenchymal glioblastoma (GBM) by controlling splicing, leading to chemoresistance. Targeting FBXO7 may offer new GBM treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Mesenchymal glioblastoma (GBM) exhibits resistance to therapy and poor prognosis.
  • The molecular mechanisms underlying the mesenchymal phenotype in GBM are not well understood.

Purpose of the Study:

  • To elucidate the role of FBXO7 in conferring mesenchymal properties and chemoresistance in GBM.
  • To investigate the mechanism by which FBXO7 influences alternative splicing in GBM.

Main Methods:

  • Investigated the interaction between FBXO7, PRMT5, and Rbfox2.
  • Analyzed FBXO7-mediated ubiquitination and stabilization of Rbfox2.
  • Assessed the impact of FBXO7 on alternative splicing of key mesenchymal genes (FoxM1, Mta1, Postn).
  • Evaluated the effect of FBXO7 on GBM stem cell self-renewal and mesenchymal transformation.
  • Examined the therapeutic potential of targeting FBXO7 in preclinical models.

Main Results:

  • FBXO7 stabilizes Rbfox2 through K63-linked ubiquitination, dependent on PRMT5-mediated arginine dimethylation.
  • FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn.
  • FBXO7 promotes GBM stem cell self-renewal and mesenchymal transformation via FoxM1 exon Va inclusion.
  • FBXO7 is stabilized by temozolomide, and its depletion sensitizes GBM xenografts to chemotherapy.

Conclusions:

  • The FBXO7-Rbfox2 axis drives mesenchymal transformation and chemoresistance in GBM through alternative splicing.
  • Targeting FBXO7 presents a promising therapeutic strategy for treating glioblastoma.
Keywords:
FBXO7alternative splicingchemoresistanceglioblastomamesenchymal transformation

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