The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells.
The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells.
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RNAm6A阅读器YTHDF2维持癌基因的表达，是胶质母细胞瘤干细胞的靶向依赖。
DOI：
10.1158/2159-8290.cd-20-0331
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发表时间：
2021-03
期刊：
影响因子：
28.2
通讯作者：
Rich JN
中科院分区：
文献类型：
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作者：
Dixit D;Prager BC;Gimple RC;Poh HX;Wang Y;Wu Q;Qiu Z;Kidwell RL;Kim LJY;Xie Q;Vitting-Seerup K;Bhargava S;Dong Z;Jiang L;Zhu Z;Hamerlik P;Jaffrey SR;Zhao JC;Wang X;Rich JN
胶质母细胞瘤是由胶质母细胞瘤干细胞（GSC）驱动的普遍致命的癌症。在这里，我们通过甲基RNA免疫沉淀，然后测序（meRIP-seq）和转录组分析来询问GSC中的N6-甲基腺苷（m6 A）mRNA修饰，发现与正常神经干细胞（NSC）相比，m6 A标记的转录物经常上调。询问m6 A调节剂，GSC显示优先表达，以及在体外和体内的依赖性，m6 A阅读器，YTHDF 2，与NSC相反。虽然已经报道YTHDF 2使mRNA不稳定，但YTHDF 2以m6 A依赖性方式稳定GSC中的MYC和VEGFA转录物。我们鉴定IGFBP 3为GSC中YTHDF 2-MYC轴的下游效应物。IGF 1/IGF 1 R抑制剂linsitinib优先靶向YTHDF 2表达细胞，抑制GSC活力而不影响NSC和损害体内胶质母细胞瘤生长。因此，YTHDF 2连接RNA表位转录组修饰和GSC生长，为YTHDF 2-MYC-IGFBP 3轴作为胶质母细胞瘤中特异性和新型治疗靶点奠定了基础。
Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSCs). Here, we interrogated N6-methyladenosine (m6A) mRNA modifications in GSCs by methyl RNA-immunoprecipitation followed by sequencing (meRIP-seq) and transcriptome analysis, finding transcripts marked by m6A often upregulated compared to normal neural stem cells (NSCs). Interrogating m6A regulators, GSCs displayed preferential expression, as well as in vitro and in vivo dependency, of the m6A reader, YTHDF2, in contrast to NSCs. While YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized MYC and VEGFA 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 in vivo 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.