M6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

Qi Cui,Hailing Shi,Peng Ye,Li Li,Qiuhao Qu,Guoqiang Sun,Guihua Sun,Zhike Lu,Yue Huang,Cai-Guang Yang,Arthur D Riggs,Chuan He,Yanhong Shi

doi:10.1016/j.celrep.2017.02.059

Abstract

SummaryRNA 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.

Highlights

More than 100 RNA modifications have been reported, including modifications within mRNAs (Machnicka et al, 2013), among which N6-methyladenosine (m6A) modification is the most prevalent internal modification in eukaryotic mRNAs (Wei et al, 1975)
We demonstrate that KD of methyltransferase-like 3 (METTL3) or methyltransferase-like 14 (METTL14) expression dramatically increased glioblastoma stem cell (GSC) growth and self-renewal
By transplanting METTL3 small hairpin RNA or METTL14 shRNA-transduced GSCs into immunodeficient non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma (NSG) mice, we show that KD of METTL3 or METTL14 expression led to substantial increase of GSC-initiated tumor progression in transplanted mouse brains

Summary

RNA modifications play critical roles in important biological processes. the functions of N6-methyladenosine (m6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. We show that m6A mRNA modification is critical for glioblastoma stem cell (GSC) self-renewal and tumorigenesis. 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. This study identifies the m6A mRNA methylation machinery as promising therapeutic targets for glioblastoma Cui et al show that m6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs) by regulating mRNA m6A enrichment and expression. An FTO inhibitor suppresses glioblastoma progression and prolongs lifespan of GSC-grafted animals, suggesting that targeting the m6A mRNA methylation machinery is a promising therapeutic tool for glioblastoma

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Experimental Procedures