The N(6)-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2.
The N(6)-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2.
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N6-甲基腺苷介导的lncRNA WEE2-AS1通过稳定RPN2促进胶质母细胞瘤进展
DOI：
10.7150/thno.74600
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Xue, Hao
中科院分区：
文献类型：
--
作者：
Li, Boyan;Zhao, Rongrong;Qiu, Wei;Pan, Ziwen;Zhao, Shulin;Qi, Yanhua;Qiu, Jiawei;Zhang, Shouji;Guo, Qindong;Fan, Yang;Xu, Hao;Li, Ming;Li, Gang;Xue, Hao
背景：胶质母细胞瘤（GBM）是最常见的原发性脑恶性肿瘤，侵袭性强，预后差。N6-甲基腺苷（m6 A）是lncRNA中最常见的甲基化修饰，在肿瘤的病理生理过程中起重要作用。然而，GBM组织中lncRNA中m6 A修饰的分布和功能尚未完全揭示。方法：采用m6 A高通量测序技术，对GBM肿瘤组织中m6 A修饰的lncRNA的表达模式进行全面分析。进行功能获得和丧失测定以研究WEE 2-AS 1在GBM中的作用。采用质谱分析、RNA下拉、RNA免疫沉淀、荧光素酶报告基因和免疫共沉淀等方法，探讨m6 A介导的WEE 2-AS 1表达上调及其下游机制。结果：首次报道了m6 A修饰的lncRNA在人GBM组织中的差异表达谱。WEE 2-AS 1被鉴定为一种新型m6 A修饰的lncRNA，可促进GBM进展，并通过m6 A阅读器IGF 2BP 3进行转录后稳定。此外，我们证实WEE 2-AS 1通过阻止CUL 2介导的RPN 2 K322泛素化促进RPN 2蛋白稳定，从而通过激活PI 3 K-Akt信号通路促进GBM恶性进展。在转化医学中，我们发现阻断WEE 2-AS 1表达可以提高达沙替尼的治疗敏感性，达沙替尼是一种经FDA批准用于GBM的中枢神经系统渗透剂。结论：总的来说，这项工作强调了WEE 2-AS 1可能作为GBM的潜在预后生物标志物和治疗靶点，其敲低显著提高了达沙替尼的疗效，为改善GBM患者的靶向联合治疗提供了一种有前景的策略。
Background: Glioblastoma (GBM) is the most common primary brain malignancy and has high aggressiveness and a poor prognosis. N6-methyladenosine (m6A) represents the most prevalent methylation modification of lncRNAs and has been shown to play important roles in the pathophysiological processes of tumors. However, the distribution and function of m6A modifications in lncRNAs in GBM tissues have not been fully revealed. Methods: The global depiction of m6A-modified lncRNA expression patterns in GBM tumor tissues was screened via m6A high-throughput sequencing. Gain- and loss-of-function assays were performed to investigate the role of WEE2-AS1 in GBM. Mass spectrometry and RNA-pulldown, RNA immunoprecipitation (RIP), luciferase reporter and coimmunoprecipitation assays were performed to explore the mechanism of m6A-mediated upregulation of WEE2-AS1 expression and the downstream mechanism promoting the malignant progression of GBM. Results: Herein, we report the differential expression profile of m6A-modified lncRNAs in human GBM tissues for the first time. WEE2-AS1 was identified as a novel m6A-modified lncRNA that promotes GBM progression and was post-transcriptionally stabilized by IGF2BP3, an m6A reader. Moreover, we confirmed that WEE2-AS1 promoted RPN2 protein stabilization by preventing CUL2-mediated RPN2 K322 ubiquitination, thereby contributing to GBM malignant progression by activating the PI3K-Akt signaling pathway. In translational medicine, we found that blocking WEE2-AS1 expression improved the therapeutic sensitivity of dasatinib, a central nervous system penetrant that is FDA-approved in GBM. Conclusions: Overall, this work highlights that WEE2-AS1 may serve as a potential prognostic biomarker and therapeutic target in GBM, the knockdown of which significantly improves the efficacy of dasatinib, providing a promising strategy for improving targeted combination therapy for GBM patients.
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影响因子：
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通讯作者：
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DOI：
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Rich JN
DOI：
10.1038/nrc.2017.105
发表时间：
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期刊：
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