RNA modifications play critical roles in important biological processes. However, the functions of N 6-methyladenosine (m 6A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m 6A 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. m 6A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m 6A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m 6A mRNA methylation machinery as promising therapeutic targets for glioblastoma.
Cui et al. show that m 6A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells (GSCs) by regulating mRNA m 6A enrichment and expression. An FTO inhibitor suppresses glioblastoma progression and prolongs lifespan of GSC-grafted animals, suggesting that targeting the m 6A mRNA methylation machinery is a promising therapeutic tool for glioblastoma.