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

Cell Rep. 2017 Mar 14;18(11):2622-2634. doi: 10.1016/j.celrep.2017.02.059.

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.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / antagonists & inhibitors
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO / metabolism
  • Animals
  • Base Sequence
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology*
  • Cell Differentiation / drug effects
  • Cell Differentiation / genetics
  • Cell Proliferation / drug effects
  • Cell Self Renewal* / drug effects
  • Cell Self Renewal* / genetics
  • Disease Progression
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Meclofenamic Acid / pharmacology
  • Methylation
  • Methyltransferases / metabolism
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • RNA / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • RNA, Messenger
  • Meclofenamic Acid
  • RNA
  • N-methyladenosine
  • Alpha-Ketoglutarate-Dependent Dioxygenase FTO
  • FTO protein, human
  • METTL14 protein, human
  • Methyltransferases
  • METTL3 protein, human
  • Adenosine