Cell Rep 2017 03;18(11):2622-2634
Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address:
RNA modifications play critical roles in important biological processes. However, the functions of N-methyladenosine (mA) mRNA modification in cancer biology and cancer stem cells remain largely unknown. Here, we show that mA 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. mA sequencing reveals that knockdown of METTL3 or METTL14 induced changes in mRNA mA enrichment and altered mRNA expression of genes (e.g., ADAM19) with critical biological functions in GSCs. In summary, this study identifies the mA mRNA methylation machinery as promising therapeutic targets for glioblastoma.