FBXO7 通过控制 Rbfox2 介导的选择性剪接赋予胶质母细胞瘤间充质特性和化疗耐药性,Advanced Science

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FBXO7 通过控制 Rbfox2 介导的选择性剪接赋予胶质母细胞瘤间充质特性和化疗耐药性
Advanced Science ( IF 14.3 ) Pub Date : 2023-10-11 , DOI: 10.1002/advs.202303561
Shangbiao Li _{1,

2} , Yanwen Chen ₂ , Yuxin Xie ₂ , Hongchao Zhan ₂ , Yu Zeng ₂ , Kunlin Zeng ₂ , Li Wang ₂ , Ziling Zhan ₂ , Cuiying Li ₂ , Liqian Zhao ₃ , Xiaoxia Chen ₂ , Yujing Tan ₁ , Zhongyong Wang ₄ , Junguo Bu ₁ , Ye Song ₃ , Fan Deng ₂ , Aidong Zhou _{1,

2,

5}

Affiliation

间充质胶质母细胞瘤 (GBM) 对放疗和化疗具有高度耐药性，与 GBM 患者较差的生存结果相关；然而，决定间充质表型的潜在机制仍不清楚。在此，研究表明FBXO7是参与帕金森病发病机制的SCF复合物的底物识别成分，通过控制Rbfox2介导的选择性剪接赋予GBM间充质特性和化学抗性。具体来说，FBXO7 在精氨酸被 PRMT5 在 Arg341 和 Arg441 上二甲基化后，通过 K63 连接的泛素链泛素化 Rbfox2 Lys249，从而导致 Rbfox2 稳定。FBXO7 控制 Rbfox2 介导的间充质基因剪接，包括FoxM1、Mta1和Postn。FBXO7诱导的外显子Va包含FoxM1，通过MEK1和核转位促进FoxM1磷酸化，从而上调CD44、CD9和ID1水平，导致GBM干细胞自我更新和间质转化。此外，FBXO7 可通过替莫唑胺稳定，并且 FBXO7 耗竭可使小鼠肿瘤异种移植物对化疗敏感。研究结果表明，FBXO7-Rbfox2 轴介导的剪接有助于间充质转化和肿瘤发生，靶向 FBXO7 代表了 GBM 治疗的潜在策略。

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

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.

更新日期：2023-10-11

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