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

• DOI: 10.1158/2159-8290.c.6548303.v1
• Publication Date: 2023-04-04T19:59:56Z
• Authors: Deobrat Dixit; Briana C. Prager; Ryan C. Gimple; Hui Xian Poh; Yang Wang; Qiulian Wu; Zhixin Qiu; Reilly L. Kidwell; Leo J.Y. Kim; Qi Xie; Kristoffer Vittin...; Shruti Bhargava; Zhen Dong; Li Jiang; Zhe Zhu; Petra Hamerlik; Samie R. Jaffrey; Jing Crystal Zhao; Xiuxing Wang; Jeremy N. Rich

<div>Abstract<p>Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated <i>N</i><sup>6</sup>-methyladenosine (m6A) mRNA modifications in GSCs methyl RNA immunoprecipitation followed sequencing and transcriptome analysis, finding transcripts marked m6A often upregulated compared with normal neural (NSC). Interrogating regulators, displayed preferential expression, as well <i>in vitro</i> vivo</i> dependency, of the reader YTHDF2, contrast to NSCs. Although YTHDF2 has been reported destabilize mRNAs, stabilized <i>MYC</i> <i>VEGFA</i> an m6A-dependent manner. We identified IGFBP3 downstream effector YTHDF2–MYC axis GSCs. The IGF1/IGF1R inhibitor linsitinib preferentially targeted YTHDF2-expressing cells, inhibiting GSC viability without affecting NSCs impairing growth. Thus, links epitranscriptomic growth, laying foundation for YTHDF2–MYC–IGFBP3 specific novel therapeutic target glioblastoma.</p>Significance:<p>Epitranscriptomics promotes cellular heterogeneity cancer. landscapes cell type–specific dependencies vulnerabilities. specifically cells. Given challenge targeting MYC, presents perturb MYC signaling glioblastoma.</p><p><i>This article highlighted In This Issue feature, p. 211</i></p></div>