m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

By Qi Cui, Hailing Shi, Peng Ye, Li Li, Qiuhao Qu, Guoqiang Sun, Guihua Sun, Zhike Lu, Yue Huang, Cai-Guang Yang and 3 more. Cell Reports, 2017

989 citations recorded by the source corpus.

Summary RNA modifications play critical roles in important biological processes. However, the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. Knockdown of METTL3 or METTL14, key components of the RNA methyltransferase complex, dramatically promotes human GSC growth, self-renewal, and tumorigenesis. In contrast, overexpression of METTL3 or inhibition of the RNA demethylase FTO suppresses GSC growth and self-renewal. Moreover, inhibition of FTO suppresses tumor progression and prolongs lifespan of GSC-grafted mice substantially. m6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/21f5b346affab28c4807fba1917ba9173e573872

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In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. P. He
4. Kate D. Meyer
5. Jiangbo W
6. Jianjun Chen
7. Huilin Huang
8. Hengyou Weng

Citations in the corpus

• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “The ethyl ester of MA has been shown to suppress glioblastoma stem cell (GSC)-initiated tumorigenesis (Cui et al., 2017).”
• Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “METTL14 also plays a tumor-suppressor role in glioblastoma, and the depletion of METTL3 or METTL14 enhances growth and self-renewal of glioblastoma stem cells and promotes tumor progression.(76) On the other hand, Weng et al.”
• m6A RNA methylation: from mechanisms to therapeutic potential (2021, positive): “METTL3/METTL14 have also been found to play oncogenic roles in glioblastoma (Cui et al , 2017).”
• The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells (2017, neutral): “Unlike in glioblastoma where m 6 A depletion promotes tumorigenesis 29, 30 , we find that METTL3 and m 6 A maintains the undifferentiated leukemic phenotype.”