m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

Cancer Cell. 2017 Apr 10;31(4):591-606.e6. doi: 10.1016/j.ccell.2017.02.013. Epub 2017 Mar 23.


The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Furthermore, a long non-coding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma.

Keywords: ALKBH5; FOXM1; glioblastoma; m(6)A modification.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • AlkB Homolog 5, RNA Demethylase / genetics
  • AlkB Homolog 5, RNA Demethylase / metabolism*
  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • ELAV-Like Protein 1 / genetics
  • ELAV-Like Protein 1 / metabolism
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Glioblastoma / genetics
  • Glioblastoma / mortality
  • Glioblastoma / pathology*
  • Male
  • Mice, Nude
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism
  • Xenograft Model Antitumor Assays


  • 3' Untranslated Regions
  • ELAV-Like Protein 1
  • ELAVL1 protein, human
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • RNA, Long Noncoding
  • ALKBH5 protein, human
  • AlkB Homolog 5, RNA Demethylase