Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells.
Novel INHAT repressor drives glioblastoma growth by promoting ribosomal DNA transcription in glioma stem cells.
复制标题
新型 INHAT 阻遏蛋白通过促进神经胶质瘤干细胞中的核糖体 DNA 转录来驱动胶质母细胞瘤生长。
DOI：
10.1093/neuonc/noac272
复制
发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Bao,Shideng
中科院分区：
文献类型：
--
作者：
Tao,Weiwei;Lei,Hong;Luo,Wenlong;Huang,Zhi;Ling,Peng;Guo,Mengyue;Wan,Lihao;Zhai,Kui;Huang,Qian;Wu,Qiulian;Xu,Shutong;Zeng,Liang;Wang,Xiuxing;Dong,Zhiqiang;Rich,JeremyN;Bao,Shideng
背景包括癌症干细胞在内的癌细胞表现出比正常细胞更高的核糖体生物发生率，以支持肿瘤中的快速细胞增殖。然而，控制神经胶质瘤干细胞（GSC）中优先核糖体生物发生的分子机制仍不清楚。在这项工作中，我们证明新型 INHAT 阻遏蛋白 (NIR) 促进核糖体 DNA (rDNA) 转录以支持 GSC 增殖和胶质母细胞瘤 (GBM) 生长，表明 NIR 是 GBM 的潜在治疗靶点。方法采用免疫印迹、免疫组织化学和免疫荧光分析来确定 NIR 在 GSC 和人 GBM 中的表达。利用 shRNA 介导的敲低，我们评估了 NIR 在 GSC 和 GSC 衍生的原位 GBM 异种移植物中的作用和功能意义。我们进一步进行了质谱分析、染色质免疫沉淀和其他生化测定，以确定 NIR 促进 GBM 进展的分子机制。结果我们的结果表明，NIR 的高表达预示着 GBM 患者的生存率较差。 NIR 在人类 GBM 的 GSC 核仁中富集。破坏 NIR 通过抑制 rDNA 转录和前核糖体 RNA 合成，显着抑制 GSC 增殖和肿瘤生长。在机制研究中，我们发现NIR通过与核仁蛋白（NCL）和核仁磷蛋白1（NPM1）这2种重要的核仁转录因子合作，激活rDNA转录以促进GSC增殖。结论我们的研究揭示了NIR介导的rDNA转录在GBM恶性进展中的关键作用，表明靶向该轴可能为GBM提供一种新的治疗策略。
BackgroundCancer cells including cancer stem cells exhibit a higher rate of ribosome biogenesis than normal cells to support rapid cell proliferation in tumors. However, the molecular mechanisms governing the preferential ribosome biogenesis in glioma stem cells (GSCs) remain unclear. In this work, we show that the novel INHAT repressor (NIR) promotes ribosomal DNA (rDNA) transcription to support GSC proliferation and glioblastoma (GBM) growth, suggesting that NIR is a potential therapeutic target for GBM.MethodsImmunoblotting, immunohistochemical and immunofluorescent analysis were used to determine NIR expression in GSCs and human GBMs. Using shRNA-mediated knockdown, we assessed the role and functional significance of NIR in GSCs and GSC-derived orthotopic GBM xenografts. We further performed mass spectrometry analysis, chromatin immunoprecipitation, and other biochemical assays to define the molecular mechanisms by which NIR promotes GBM progression.ResultsOur results show that high expression ofNIRpredicts poor survival in GBM patients. NIR is enriched in the nucleoli of GSCs in human GBMs. DisruptingNIRmarkedly suppresses GSC proliferation and tumor growth by inhibiting rDNA transcription and pre-ribosomal RNA synthesis. In mechanistic studies, we find that NIR activates rDNA transcription to promote GSC proliferation by cooperating with Nucleolin (NCL) and Nucleophosmin 1 (NPM1), 2 important nucleolar transcription factors.ConclusionsOur study uncovers a critical role of NIR-mediated rDNA transcription in the malignant progression of GBM, indicating that targeting this axis may provide a novel therapeutic strategy for GBM.