m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells

RNA modifications play critical roles in important biological processes. However, the functions of N(6)-methyladenosine (m(6)A) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that m(6)A 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(6)A sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA m(6)A enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the m(6)A mRNA methylation machinery as promising therapeutic targets for glioblastoma.