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

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 Vitting-Seerup, Shruti Bhargava, Zhen Dong, Li Jiang, Zhe Zhu, Petra Hamerlik, Samie R. Jaffrey, Jing Crystal Zhao, Xiuxing Wang and Jeremy N. Rich
Deobrat Dixit
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Briana C. Prager
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
2Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
3Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio.
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Ryan C. Gimple
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
2Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
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Hui Xian Poh
4Department of Pharmacology, Weill Cornell Medicine, New York, New York.
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Yang Wang
5Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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  • ORCID record for Yang Wang
Qiulian Wu
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Zhixin Qiu
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Reilly L. Kidwell
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Leo J.Y. Kim
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
2Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
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Qi Xie
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Kristoffer Vitting-Seerup
6Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
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Shruti Bhargava
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Zhen Dong
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Li Jiang
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Zhe Zhu
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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Petra Hamerlik
6Brain Tumor Biology Group, Danish Cancer Society Research Center, Copenhagen, Denmark.
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Samie R. Jaffrey
4Department of Pharmacology, Weill Cornell Medicine, New York, New York.
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Jing Crystal Zhao
5Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
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  • For correspondence: drjeremyrich@gmail.com xiuxingwang81@163.com czhao@sbpdiscovery.org
Xiuxing Wang
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
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  • For correspondence: drjeremyrich@gmail.com xiuxingwang81@163.com czhao@sbpdiscovery.org
Jeremy N. Rich
1Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.
7Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, California.
8Department of Neurology, University of Pittsburgh, Pittsburgh, PA; UPMC Hillman Cancer Center, Pittsburgh, PA.
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  • For correspondence: drjeremyrich@gmail.com xiuxingwang81@163.com czhao@sbpdiscovery.org
DOI: 10.1158/2159-8290.CD-20-0331 Published February 2021
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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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2021;11:480–99

  • Received March 17, 2020.
  • Revision received August 9, 2020.
  • Accepted September 30, 2020.
  • Published first October 6, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Discovery: 11 (2)
February 2021
Volume 11, Issue 2
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The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells
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 Vitting-Seerup, Shruti Bhargava, Zhen Dong, Li Jiang, Zhe Zhu, Petra Hamerlik, Samie R. Jaffrey, Jing Crystal Zhao, Xiuxing Wang and Jeremy N. Rich
Cancer Discov February 1 2021 (11) (2) 480-499; DOI: 10.1158/2159-8290.CD-20-0331

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The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in Glioblastoma Stem Cells
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 Vitting-Seerup, Shruti Bhargava, Zhen Dong, Li Jiang, Zhe Zhu, Petra Hamerlik, Samie R. Jaffrey, Jing Crystal Zhao, Xiuxing Wang and Jeremy N. Rich
Cancer Discov February 1 2021 (11) (2) 480-499; DOI: 10.1158/2159-8290.CD-20-0331
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