O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner.

IF 16.4 1区 医学 Q1 CLINICAL NEUROLOGY
Jiawei Qiu, Rongrong Zhao, Caizhi Ma, Qingtong Wang, Boyan Li, Yanhua Qi, Ziwen Pan, Shulin Zhao, Shaobo Wang, Zijie Gao, Xiaofan Guo, Wei Qiu, Weijie Tang, Xing Guo, Lin Deng, Hao Xue, Gang Li
{"title":"O-GlcNAcylation stabilized WTAP promotes GBM malignant progression in an N6-methyladenosine-dependent manner.","authors":"Jiawei Qiu, Rongrong Zhao, Caizhi Ma, Qingtong Wang, Boyan Li, Yanhua Qi, Ziwen Pan, Shulin Zhao, Shaobo Wang, Zijie Gao, Xiaofan Guo, Wei Qiu, Weijie Tang, Xing Guo, Lin Deng, Hao Xue, Gang Li","doi":"10.1093/neuonc/noae268","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Interactions between mesenchymal glioblastoma stem cells (MES GSCs) and myeloid-derived macrophages (MDMs) shape the tumor-immunosuppressive microenvironment (TIME), promoting the progression of glioblastoma (GBM). N6-methyladenosine (m6A) plays important roles in the tumor progression. However, the mechanism of m6A in shaping the TIME of GBM remains elusive.</p><p><strong>Methods: </strong>Single-cell RNA sequencing and bulk RNA-seq datasets were employed to identify the critical role of WTAP in interactions between MES GBM and MDMs. The biological function of WTAP was confirmed both in vitro and in vivo. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted.</p><p><strong>Results: </strong>Here, we identified that m6A methyltransferase Wilms' Tumor 1-Associated Protein (WTAP), whose protein stability could be synergistically enhanced via OGT-mediated O-GlcNAcylation and USP7-mediated de-ubiquitination, promoted LOXL2 m6A modification to enhance its mRNA stabilization in an IGF2BP2-dependent manner, upregulating secretion of LOXL2 protein (sLOXL2). sLOXL2 then interacted with integrin α5β1 on GSCs to activate FAK-ERK signaling, inducing mesenchymal transition of GSCs in an autocrine manner. Meanwhile, sLOXL2 also activated the integrin α5β1-FAK-ERK axis in MDMs, which promoted M2-like MDM phenotypes in a paracrine pathway, thereby contributing to T cell exhaustion to induce GBM immune escape. In translational medicine, combinations of the OGT inhibitor by targeting WTAP expression and the LOXL2 antagonist by disrupting MES GSC and MDM interactions showed favorable outcomes to the anti-PD1 immunotherapy.</p><p><strong>Conclusions: </strong>WTAP plays critical roles in mesenchymal transition of GSCs and formation of TIME, highlighting the therapeutic potential of targeting WTAP and its downstream effectors to enhance the efficacy of immunotherapy.</p>","PeriodicalId":19377,"journal":{"name":"Neuro-oncology","volume":" ","pages":""},"PeriodicalIF":16.4000,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuro-oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1093/neuonc/noae268","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Background: Interactions between mesenchymal glioblastoma stem cells (MES GSCs) and myeloid-derived macrophages (MDMs) shape the tumor-immunosuppressive microenvironment (TIME), promoting the progression of glioblastoma (GBM). N6-methyladenosine (m6A) plays important roles in the tumor progression. However, the mechanism of m6A in shaping the TIME of GBM remains elusive.

Methods: Single-cell RNA sequencing and bulk RNA-seq datasets were employed to identify the critical role of WTAP in interactions between MES GBM and MDMs. The biological function of WTAP was confirmed both in vitro and in vivo. Mechanistically, mass spectrum, RNA immunoprecipitation (RIP), and co-immunoprecipitation assays were conducted.

Results: Here, we identified that m6A methyltransferase Wilms' Tumor 1-Associated Protein (WTAP), whose protein stability could be synergistically enhanced via OGT-mediated O-GlcNAcylation and USP7-mediated de-ubiquitination, promoted LOXL2 m6A modification to enhance its mRNA stabilization in an IGF2BP2-dependent manner, upregulating secretion of LOXL2 protein (sLOXL2). sLOXL2 then interacted with integrin α5β1 on GSCs to activate FAK-ERK signaling, inducing mesenchymal transition of GSCs in an autocrine manner. Meanwhile, sLOXL2 also activated the integrin α5β1-FAK-ERK axis in MDMs, which promoted M2-like MDM phenotypes in a paracrine pathway, thereby contributing to T cell exhaustion to induce GBM immune escape. In translational medicine, combinations of the OGT inhibitor by targeting WTAP expression and the LOXL2 antagonist by disrupting MES GSC and MDM interactions showed favorable outcomes to the anti-PD1 immunotherapy.

Conclusions: WTAP plays critical roles in mesenchymal transition of GSCs and formation of TIME, highlighting the therapeutic potential of targeting WTAP and its downstream effectors to enhance the efficacy of immunotherapy.

o - glcn酰化稳定的WTAP以n6 -甲基腺苷依赖的方式促进GBM恶性进展。
背景:间充质胶质母细胞瘤干细胞(MES GSCs)和髓源性巨噬细胞(MDMs)之间的相互作用形成肿瘤免疫抑制微环境(TIME),促进胶质母细胞瘤(GBM)的进展。n6 -甲基腺苷(m6A)在肿瘤进展中起重要作用。然而,m6A对GBM TIME形成的机制尚不清楚。方法:采用单细胞RNA测序和大量RNA-seq数据集来确定WTAP在MES GBM和MDMs相互作用中的关键作用。体外和体内实验均证实了WTAP的生物学功能。在机制上,进行了质谱、RNA免疫沉淀(RIP)和共免疫沉淀试验。结果:我们发现m6A甲基转移酶Wilms' Tumor 1-Associated Protein (WTAP),其蛋白稳定性可通过ogt介导的o - glcn酰化和usp7介导的去泛素化协同增强,促进LOXL2 m6A修饰,以依赖igf2bp2的方式增强其mRNA稳定性,上调LOXL2蛋白(sLOXL2)的分泌。然后sLOXL2与GSCs上的整合素α5β1相互作用,激活FAK-ERK信号,以自分泌方式诱导GSCs的间质转化。同时,sLOXL2还激活MDM中的整合素α5β1-FAK-ERK轴,通过旁分泌途径促进m2样MDM表型,从而促进T细胞衰竭,诱导GBM免疫逃逸。在转化医学中,通过靶向WTAP表达的OGT抑制剂和通过破坏MES - GSC和MDM相互作用的LOXL2拮抗剂的组合显示出抗pd1免疫治疗的良好结果。结论:WTAP在GSCs的间质转化和TIME的形成中起关键作用,提示靶向WTAP及其下游效应物提高免疫治疗效果的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Neuro-oncology
Neuro-oncology 医学-临床神经学
CiteScore
27.20
自引率
6.30%
发文量
1434
审稿时长
3-8 weeks
期刊介绍: Neuro-Oncology, the official journal of the Society for Neuro-Oncology, has been published monthly since January 2010. Affiliated with the Japan Society for Neuro-Oncology and the European Association of Neuro-Oncology, it is a global leader in the field. The journal is committed to swiftly disseminating high-quality information across all areas of neuro-oncology. It features peer-reviewed articles, reviews, symposia on various topics, abstracts from annual meetings, and updates from neuro-oncology societies worldwide.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信