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

in Cancer discovery by 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, Jeremy N Rich

TLDR

  • The study identified the m6A reader YTHDF2 as a key regulator of glioblastoma stem cell growth, presenting a novel therapeutic target for the treatment of glioblastoma.
  • The study highlights the importance of epitranscriptomics in promoting cellular heterogeneity in cancer.
  • The study suggests that targeting YTHDF2 with linsitinib could be a potential therapy for glioblastoma.

Abstract

Glioblastoma is a universally lethal cancer driven by glioblastoma stem cells (GSC). Here, we interrogated-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 asanddependency, of the m6A reader YTHDF2, in contrast to NSCs. Although YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilizedandtranscripts 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 impairingglioblastoma 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 stabilizedmRNA specifically in cancer stem cells. Given the challenge of targeting MYC, YTHDF2 presents a therapeutic target to perturb MYC signaling in glioblastoma..

Overview

  • Study of m6A mRNA modifications in glioblastoma stem cells (GSCs) and normal neural stem cells (NSCs)
  • Analysis of m6A regulators, specifically the m6A reader YTHDF2, and its relationship with the transcriptome and cellular behavior
  • Examination of the therapeutic potential of targeting YTHDF2 in glioblastoma

Comparative Analysis & Findings

  • Transcripts marked by m6A were often upregulated in GSCs compared to NSCs
  • GSCs displayed preferential expression and dependency on the m6A reader YTHDF2, in contrast to NSCs
  • Although YTHDF2 has been reported to destabilize mRNAs, YTHDF2 stabilized and transcripts in GSCs in an m6A-dependent manner

Implications and Future Directions

  • The YTHDF2-MYC axis is a specific and novel therapeutic target in glioblastoma
  • The study highlights the importance of epitranscriptomics in promoting cellular heterogeneity in cancer
  • Future studies could investigate the use of linsitinib, an IGF1/IGF1R inhibitor, as a potential therapeutic agent in glioblastoma
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