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RNA m6A 阅读器 YTHDF2 维持致癌基因表达，是神经胶质瘤干细胞的一个可靶向依赖性。

The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells.

机构信息

Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.

Department of Pathology, Case Western Reserve University, Cleveland, Ohio.

出版信息

Cancer Discov. 2021 Feb;11(2):480-499. doi: 10.1158/2159-8290.CD-20-0331. Epub 2020 Oct 6.

DOI:10.1158/2159-8290.CD-20-0331
PMID:33023892
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8110214/
Abstract

Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated -methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA immunoprecipitation followed by sequencing and transcriptome analysis, finding transcripts marked by m6A often upregulated compared with normal neural stem cells (NSC). Interrogating m6A regulators, GSCs displayed preferential expression, as well as and dependency, of the m6A reader YTHDF2, in contrast to NSCs. Although YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized and transcripts in GSCs in an m6A-dependent manner. We identified IGFBP3 as a downstream effector of the YTHDF2-MYC axis in GSCs. The IGF1/IGF1R inhibitor linsitinib preferentially targeted YTHDF2-expressing cells, inhibiting GSC viability without affecting NSCs and impairing glioblastoma growth. Thus, YTHDF2 links RNA epitranscriptomic modifications and GSC growth, laying the foundation for the YTHDF2-MYC-IGFBP3 axis as a specific and novel therapeutic target in glioblastoma. SIGNIFICANCE: Epitranscriptomics promotes cellular heterogeneity in cancer. RNA m6A landscapes of cancer and NSCs identified cell type-specific dependencies and therapeutic vulnerabilities. The m6A reader YTHDF2 stabilized mRNA specifically in cancer stem cells. Given the challenge of targeting MYC, YTHDF2 presents a therapeutic target to perturb MYC signaling in glioblastoma..

摘要

胶质母细胞瘤是一种普遍致命的癌症，由胶质母细胞瘤干细胞 (GSC) 驱动。在这里，我们通过甲基 RNA 免疫沉淀 followed by sequencing 和转录组分析来研究 GSCs 中的 -甲基腺苷 (m6A) mRNA 修饰，发现与正常神经干细胞 (NSC) 相比，m6A 标记的转录本经常上调。在探究 m6A 调节因子时，GSCs 表现出对 m6A 阅读器 YTHDF2 的优先表达，以及对 和 的依赖性，而 NSCs 则没有。尽管 YTHDF2 已被报道可使 mRNA 不稳定，但 YTHDF2 以 m6A 依赖的方式稳定 GSCs 中的 和 转录本。我们确定 IGFBP3 是 GSCs 中 YTHDF2-MYC 轴的下游效应物。IGF1/IGF1R 抑制剂 linsitinib 优先靶向表达 YTHDF2 的细胞，抑制 GSC 活力而不影响 NSCs 并损害 胶质母细胞瘤的生长。因此，YTHDF2 将 RNA 表转录组修饰与 GSC 生长联系起来，为 YTHDF2-MYC-IGFBP3 轴作为胶质母细胞瘤的特异性和新型治疗靶点奠定了基础。意义：表观转录组促进癌症中的细胞异质性。癌症和 NSCs 的 RNA m6A 图谱确定了细胞类型特异性的依赖性和治疗弱点。m6A 阅读器 YTHDF2 特异性地在癌症干细胞中稳定 mRNA。鉴于靶向 MYC 的挑战，YTHDF2 提供了一个治疗靶点，可扰乱胶质母细胞瘤中的 MYC 信号。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/9e03cdfc789e/nihms-1635607-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/74d5f42ac821/nihms-1635607-f0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/b8bff88fff15/nihms-1635607-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/7db3c12238c3/nihms-1635607-f0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/9e03cdfc789e/nihms-1635607-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/74d5f42ac821/nihms-1635607-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/d409457a5655/nihms-1635607-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/dd7640d0e814/nihms-1635607-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/b8bff88fff15/nihms-1635607-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/7db3c12238c3/nihms-1635607-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/943c960ae01d/nihms-1635607-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fe78/8110214/9e03cdfc789e/nihms-1635607-f0007.jpg

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Cell. 2020 Jun 25;181(7):1582-1595.e18. doi: 10.1016/j.cell.2020.05.012. Epub 2020 Jun 2.
3
Limits in the detection of mA changes using MeRIP/mA-seq.使用 MeRIP/mA-seq 检测 mA 变化的局限性。
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Acta Pharmacol Sin. 2025 Aug 21. doi: 10.1038/s41401-025-01631-6.
4
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Transl Cancer Res. 2025 Jul 30;14(7):4219-4242. doi: 10.21037/tcr-2024-2616. Epub 2025 Jul 27.
5
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Front Endocrinol (Lausanne). 2025 Jul 25;16:1530578. doi: 10.3389/fendo.2025.1530578. eCollection 2025.
6
Phosphodiesterase 1A physically interacts with YTHDF2 and reinforces the progression of non-small cell lung cancer.磷酸二酯酶1A与YTHDF2发生物理相互作用并促进非小细胞肺癌的进展。
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4
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8
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9
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