Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
Neuro Oncol. 2021 Oct 1;23(10):1693-1708. doi: 10.1093/neuonc/noab126.
The glioblastoma (GBM) mesenchymal (MES) phenotype, induced by NF-κB activation, is characterized by aggressive tumor progression and poor clinical outcomes. Our previous analysis indicated that MES GBM has a unique alternative splicing (AS) pattern; however, the underlying mechanism remains obscure. We aimed to reveal how splicing regulation contributes to MES phenotype promotion in GBM.
We screened novel candidate splicing factors that participate in NF-κB activation and MES phenotype promotion in GBM. In vitro and in vivo assays were used to explore the function of RSRP1 in MES GBM.
Here, we identified that arginine/serine-rich protein 1 (RSRP1) promotes the MES phenotype by facilitating GBM cell invasion and apoptosis resistance. Proteomic, transcriptomic, and functional analyses confirmed that RSRP1 regulates AS in MES GBM through mediating spliceosome assembly. One RSRP1-regulated AS event resulted in skipping PARP6 exon 18 to form truncated, oncogenic PARP6-s. This isoform was unable to effectively suppress NF-κB. Cotreatment of cultured GBM cells and GBM tumor-bearing mice with spliceosome and NF-κB inhibitors exerted a synergistic effect on MES GBM growth.
We identified a novel mechanism through which RSRP1-dependent splicing promotes the GBM MES phenotype. Targeting AS via RSRP1-related spliceosomal factors might constitute a promising treatment for GBM.
由 NF-κB 激活诱导的胶质母细胞瘤（GBM）间质（MES）表型，其特征是肿瘤进展迅速且临床预后较差。我们之前的分析表明，MES GBM 具有独特的选择性剪接（AS）模式；然而，其潜在机制尚不清楚。我们旨在揭示剪接调控如何促进 GBM 中的 MES 表型。
我们筛选了参与 NF-κB 激活和 GBM 中 MES 表型促进的新型候选剪接因子。体外和体内实验用于研究 RSRP1 在 MES GBM 中的功能。
在这里，我们发现精氨酸/丝氨酸丰富蛋白 1（RSRP1）通过促进 GBM 细胞侵袭和抗凋亡来促进 MES 表型。蛋白质组学、转录组学和功能分析证实，RSRP1 通过调节剪接体组装来调节 MES GBM 中的 AS。RSRP1 调节的一个 AS 事件导致 PARP6 外显子 18 跳过，形成截短的、致癌的 PARP6-s。这种异构体不能有效地抑制 NF-κB。在培养的 GBM 细胞和 GBM 荷瘤小鼠中同时使用剪接体和 NF-κB 抑制剂对 MES GBM 的生长具有协同作用。
我们确定了一种新的机制，即 RSRP1 依赖性剪接促进 GBM 的 MES 表型。通过与 RSRP1 相关的剪接体因子靶向 AS，可能成为治疗 GBM 的一种有前途的方法。
