2. Academic Validation
  3. 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

  • Cancer Discov. 2021 Feb;11(2):480-499. doi: 10.1158/2159-8290.CD-20-0331.
Deobrat Dixit 1,  Briana C Prager 1 2 3,  Ryan C Gimple 1 2,  Hui Xian Poh 4,  Yang Wang 5,  Qiulian Wu 1,  Zhixin Qiu 1,  Reilly L Kidwell 1,  Leo J Y Kim 1 2,  Qi Xie 1,  Kristoffer Vitting-Seerup 6,  Shruti Bhargava 1,  Zhen Dong 1,  Li Jiang 1,  Zhe Zhu 1,  Petra Hamerlik 6,  Samie R Jaffrey 4,  Jing Crystal Zhao 7,  Xiuxing Wang 8,  Jeremy N Rich 8 9 10
Affiliations

Affiliations

  • 1 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
  • 2 Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
  • 3 Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
  • 4 Department of Pharmacology, Weill Cornell Medicine, New York, New York.
  • 5 Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  • 6 Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
  • 7 Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. [email protected] [email protected] [email protected].
  • 8 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California. [email protected] [email protected] [email protected].
  • 9 Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, California.
  • 10 Department of Neurology, University of Pittsburgh, Pittsburgh, PA; UPMC Hillman Cancer Center, Pittsburgh, PA.
PMID: 33023892 DOI: 10.1158/2159-8290.CD-20-0331
Abstract

Glioblastoma is a universally lethal Cancer driven by glioblastoma stem cells (GSC). Here, we interrogated N 6-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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