m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program.
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.
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Sicong
S
Zhang
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Boxuan Simen
BS
Zhao
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Aidong
A
Zhou
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Kangyu
K
Lin
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Shaoping
S
Zheng
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA.
Zhike
Z
Lu
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Yaohui
Y
Chen
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Erik P
EP
Sulman
Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA; Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Keping
K
Xie
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
Oliver
O
Bögler
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sadhan
S
Majumder
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA.
Chuan
C
He
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Cancer Biology, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA. Electronic address: suhuang@mdanderson.org.
Suyun
S
Huang
D020413:3' Untranslated Regions; D000071502:AlkB Homolog 5, RNA Demethylase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000067780:ELAV-Like Protein 1 / Q000235:genetics / Q000378:metabolism; D000072278:Forkhead Box Protein M1 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D020413:3' Untranslated Regions; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D062085:RNA, Long Noncoding; C559920:ALKBH5 protein, human; D000071502:AlkB Homolog 5, RNA Demethylase
ALKBH5; FOXM1; glioblastoma; m(6)A modification