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

Abstract

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.

Keywords: FTO inhibitor; METTL14; METTL3; glioblastoma stem cells; m(6)A modification.