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首页> 外文期刊>Cancer Cell >Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma
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Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma

机译：在致癌成分中的调节内含子的协调剪接在恶性胶质瘤中产生了可利用的脆弱性

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摘要

Summary Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in?vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in?vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an exploitable cancer vulnerability. Graphical Abstract Display Omitted Highlights ? DI splicing is a regulated pathway promoting proliferation gene expression ? GBMs assume control of the DI pathway, creating an exploitable vulnerability ? PRMT5 inhibition induces DI inclusion and yields potent anti-tumor activity ? CLNS1A/RIOK1 ratio is a predictive biomarker for PRMT5 inhibitor sensitivity Braun et?al. show that glioblastoma is selectively sensitive to the inhibition of PRMT5 and identify a predictive biomarker for this sensitivity. PRMT5 inhibition primarily disrupts the removal of detained introns, which results in the reduction of functional transcripts of mainly proliferation-associated genes.
机译：发明内容Glioblastoma（GBM）是一种毁灭性的恶性肿瘤，治疗少数。我们在IN in？体内GBM shRNA筛网中识别PRMT5，并显示PRMT5敲低或抑制在β体内GBM肿瘤中，包括患者衍生的异种移植物。途径分析意味着细胞PRMT5依赖性的剪接，并且我们鉴定了一种预测PRMT5抑制敏感性的生物标志物。我们发现PRMT5缺乏主要破坏拘留内含子（DIS）的去除。这种受损的DI剪接会影响增殖基因，其下调与细胞周期缺陷，衰老和/或细胞凋亡一致。我们进一步表明，在神经发生过程中，DI程序正在进行保存并运作，表明它们代表了生理调节机制。集体，这些调查结果揭示了一个PRMT5监管的二拼接计划，作为可利用的癌症脆弱性。图形抽象显示省略了亮点？ DI拼接是一种促进增殖基因表达的调节途径？ GBMS假设控制DI路径，创建可利用的漏洞？ PRMT5抑制诱导DI夹杂物并产生有效的抗肿瘤活性吗？ CLNS1A / RIOK1的比例是PRMT5抑制剂敏感性Braun等的预测生物标志物。表明胶质母细胞瘤对PRMT5的抑制是可选择性敏感的，并鉴定这种敏感性的预测生物标志物。 PRMT5抑制主要破坏释放内含子的去除，这导致主要增殖相关基因的功能转录物的降低。

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  • 来源
    《Cancer Cell》 |2017年第4期|共16页
  • 作者

    Christian J. Braun; Monica Stanciu; Paul L. Boutz; Jesse C. Patterson; David Calligaris; Fumi Higuchi; Rachit Neupane; Silvia Fenoglio; Daniel P. Cahill; Hiroaki Wakimoto; Nathalie Y.R. Agar; Michael B. Yaffe; Phillip A. Sharp; Michael T. Hemann; Jacqueline A. Lees;

  • 作者单位

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    Department of Neurosurgery Brigham and Women's Hospital Harvard Medical School;

    Department of Neurosurgery Massachusetts General Hospital Harvard Medical School;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    Department of Neurosurgery Massachusetts General Hospital Harvard Medical School;

    Department of Neurosurgery Massachusetts General Hospital Harvard Medical School;

    Department of Neurosurgery Brigham and Women's Hospital Harvard Medical School;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

    The David H. Koch Institute for Integrative Cancer Research and Department of Biology;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 肿瘤学;
  • 关键词

    splicing addiction; GBM; PRMT5; EPZ015666; biomarker; CLNS1A; RIOK1;

    机译：拼接成瘾;GBM;PRMT5;EPZ015666;生物标志物;CLNS1A;RIOK1;

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