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

作者：Li, Shangbiao; Chen, Yanwen; Xie, Yuxin; Zhan, Hongchao; Zeng, Yu; Zeng, Kunlin; Wang, Li; Zhan, Ziling; Li, Cuiying; Zhao, Liqian; Chen, Xiaoxia; Tan, Yujing; Wang, Zhongyong; Bu, Junguo; Song, Ye; Deng, Fan; Zhou, Aidong^*

来源：Advanced Science, 2023, 10(33).

DOI：10.1002/advs.202303561

• alternative splicing
• chemoresistance
• FBXO7
• glioblastoma
• mesenchymal transformation

Mesenchymal glioblastoma (GBM) is highly resistant to radio-and chemotherapy and correlates with worse survival outcomes in GBM patients; however, the underlying mechanism determining the mesenchymal phenotype remains largely unclear. Herein, it is revealed that FBXO7, a substrate-recognition component of the SCF complex implicated in the pathogenesis of Parkinson's disease, confers mesenchymal properties and chemoresistance in GBM by controlling Rbfox2-mediated alternative splicing. Specifically, FBXO7 ubiquitinates Rbfox2 Lys249 through K63-linked ubiquitin chains upon arginine dimethylation at Arg341 and Arg441 by PRMT5, leading to Rbfox2 stabilization. FBXO7 controls Rbfox2-mediated splicing of mesenchymal genes, including FoxM1, Mta1, and Postn. FBXO7-induced exon Va inclusion of FoxM1 promotes FoxM1 phosphorylation by MEK1 and nuclear translocation, thereby upregulates CD44, CD9, and ID1 levels, resulting in GBM stem cell self-renewal and mesenchymal transformation. Moreover, FBXO7 is stabilized by temozolomide, and FBXO7 depletion sensitizes tumor xenografts in mice to chemotherapy. The findings demonstrate that the FBXO7-Rbfox2 axis-mediated splicing contributes to mesenchymal transformation and tumorigenesis, and targeting FBXO7 represents a potential strategy for GBM treatment. @@@ The authors discover that FBXO7 confers mesenchymal properties and chemoresistance in glioblastoma. FBXO7 upregulation in mesenchymal glioblastoma stabilizes Rbfox2 through K63-linked ubiquitination after its arginine dimethylation by PRMT5, and thus controls Rbfox2-mediated splicing of mesenchymal genes, resulting in glioblastoma stem cell self-renewal, mesenchymal transformation, and chemoresistance. Targeting the FBXO7-Rbfox2 axis represents a potential strategy for glioblastoma treatment.image

• 单位
  苏州大学; 南方医科大学