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

Authors: 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 - Cell Reports 2017 cited by 1,334

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.