The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes.
The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes.
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DOI：
10.1080/15476286.2023.2221511
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发表时间：
2023-01
期刊：
影响因子：
4.1
通讯作者：
Galante, Pedro A. F.
中科院分区：
文献类型：
--
作者：
Barreiro, Rodrigo A. S.;Guardia, Gabriela D. A.;Meliso, Fabiana M.;Lei, Xiufen;Li, Wei-Qing;Savio, Andre;Fellermeyer, Martin;Conceicao, Helena B.;Mercuri, Rafael L. V.;Landry, Tesha;Qiao, Mei;Blazquez, Lorea;Ule, Jernej;Penalva, Luiz O. F.;Galante, Pedro A. F.
外显子连接复合物（EJC）在RNA的整个生命周期中起着关键作用，并且在神经系统中特别相关。我们研究了两个EJC成员，旁系同源物MAGOH和MAGOHB在脑肿瘤发展中的作用。在14种肿瘤类型中观察到MAGOH/MAGOHB高表达;与正常组织相比，胶质母细胞瘤（GBM）表现出最大的差异。MAGOH/MAGOHB表达增加与胶质瘤患者预后不良相关，而MAGOH/MAGOHB的敲低影响不同的癌症表型。GBM细胞中MAGOH/MAGOHB表达的减少导致剪接谱的改变，包括多个外显子的重新剪接和跳跃。EJC蛋白的结合谱表明，MAGOH/MAGOHB敲除影响的外显子平均积累较少的复合物，提供了一个可能的解释，其敏感性MAGOH/MAGOHB敲除。显示剪接谱改变的转录物（基因）主要涉及细胞分裂、细胞周期、剪接和翻译。我们提出，需要高MAGOH/MAGOHB水平，以保障在需要增加细胞增殖（大脑发育和GBM生长）的情况下高需求的基因剪接，确保有效的细胞分裂，细胞周期调控和基因表达（剪接和翻译）。由于分化的神经元细胞不需要增加MAGOH/MAGOHB表达，靶向这些旁系同源物是治疗GBM的潜在选择。
The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumour development. High MAGOH/MAGOHB expression was observed in 14 tumour types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.
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