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

Abstract

Summary 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.

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…Reduction in m 6 A level induced by METTL3 silencing led to the up‐regulation of a group of oncogenes such as ADAM19, EPHA3 and KLF4, but a down‐regulation of tumour suppressors including CDKN2A, BRCA2 and TP53I11. Besides, in terms of phenotypes, knockdown of METTL3 promoted GSCs growth and self‐renewal as well as tumour progression, and vice versa 47. It indicated that METTL3 was possibly a tumour suppressor of glioblastoma.…”

“…METTL14 performed tumour suppressor functions similar to that of METTL3 in the development of GSCs by targeting mRNA levels of ADAM19, EPHA3 and KLF4 47. Wang et al.…”

“…Glioblastoma is an aggressive primary brain tumour in adults and has no significant improvement in survival rate so far 46. Previous studies strongly indicated the role of m 6 A methylation in self‐renewal and tumorigenesis of glioblastoma stem cells (GSCs) 47. Reduction in m 6 A level induced by METTL3 silencing led to the up‐regulation of a group of oncogenes such as ADAM19, EPHA3 and KLF4, but a down‐regulation of tumour suppressors including CDKN2A, BRCA2 and TP53I11.…”

RNA m6A modification and its function in diseases

“…m 6 A demethylases also play essential roles in cancer. Both FTO and ALKBH5 could promote tumorigenesis of GSC [42,71]. Under hypoxia conditions, ALKBH5 mediated m 6 A demethylation of pluripotency factors, such as NANOG and KLF4, thereby promoting the breast cancer stem cell (BCSC) phenotype [42,60].…”

Role of RNA modifications in brain and behavior

“…76–78 However, studies of the relationship of RNA modifications to neuropsychiatric disorders are just beginning.…”