Статья

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

Deobrat Dixit1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaBriana C. Prager1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaRyan C. Gimple1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaHui Xian Poh4Department of Pharmacology, Weill Cornell Medicine, New York, New YorkYang Wang5Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CaliforniaQiulian Wu1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaZhixin Qiu1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaReilly L. Kidwell1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaLeo J.Y. Kim1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaQi Xie1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaKristoffer Vitting‐Seerup6Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, DenmarkShruti Bhargava1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaZhen Dong1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaLi Jiang1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaZhe Zhu1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, CaliforniaPetra Hamerlik6Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, DenmarkSamie R. Jaffrey4Department of Pharmacology, Weill Cornell Medicine, New York, New YorkJing Zhao5Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CaliforniaJeremy N. Rich1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California

2020en

ABI

Аннотация

Abstract Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated N6-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 in vitro and in vivo dependency, of the m6A reader YTHDF2, in contrast to NSCs. Although 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. 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 MYC mRNA specifically in cancer stem cells. Given the challenge of targeting MYC, YTHDF2 presents a therapeutic target to perturb MYC signaling in glioblastoma. This article is highlighted in the In This Issue feature, p. 211

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Идентификаторы

DOI: 10.1158/2159-8290.cd-20-0331

Цитирования и источники

Цитирований: 2Использованных источников: 0

Показатели — AkademScholar