Home LiteratureArticle Details
PMID: 28344040 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

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

Cancer cell ·Vol. 31 ·No. 4 ·2017-00-10 ·Pages 591-606.e6

Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O, Majumder S, He C, Huang S

Abstract

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
MeSH Terms
3' Untranslated Regions AlkB Homolog 5, RNA Demethylase/genetics,metabolism Animals Brain Neoplasms/genetics,mortality,pathology Cell Line, Tumor Cell Proliferation ELAV-Like Protein 1/genetics,metabolism Forkhead Box Protein M1/genetics,metabolism Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Glioblastoma/genetics,mortality,pathology Male Mice, Nude Neoplastic Stem Cells/metabolism,pathology RNA, Long Noncoding/genetics,metabolism Xenograft Model Antitumor Assays
Chemicals
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
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Zhang Sicong
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.
Zhao Boxuan Simen
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.
Zhou Aidong
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lin Kangyu
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Zheng Shaoping
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lu Zhike
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.
Chen Yaohui
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Sulman Erik P
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Xie Keping
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.
Bögler Oliver
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.
Majumder Sadhan
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
He Chuan
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.
Huang Suyun
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.
References (50)
50 references, click to expand
  1. High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing.
    Angew Chem Int Ed Engl. 2015 Jan 26;54(5):1587-90 PMID: 25491922
  2. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis.
    Cell Res. 2014 Dec;24(12 ):1403-19 PMID: 25412662
  3. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency.
    Cell. 2015 Jun 4;161(6):1388-99 PMID: 26046440
  4. Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells.
    Cancer Cell. 2015 Oct 12;28(4):441-55 PMID: 26461092
  5. m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells.
    Cell Stem Cell. 2014 Dec 4;15(6):707-19 PMID: 25456834
  6. Physical isolation of nascent RNA chains transcribed by RNA polymerase II: evidence for cotranscriptional splicing.
    Mol Cell Biol. 1994 Nov;14(11):7219-25 PMID: 7523861
  7. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons.
    Cell. 2012 Jun 22;149(7):1635-46 PMID: 22608085
  8. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
    Cancer Cell. 2009 Jun 2;15(6):501-13 PMID: 19477429
  9. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.
    Mol Cell. 2013 Jan 10;49(1):18-29 PMID: 23177736
  10. 5' UTR m(6)A Promotes Cap-Independent Translation.
    Cell. 2015 Nov 5;163(4):999-1010 PMID: 26593424
  11. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO.
    Nat Chem Biol. 2011 Oct 16;7(12 ):885-7 PMID: 22002720
  12. N6-methyladenosine-dependent regulation of messenger RNA stability.
    Nature. 2014 Jan 2;505(7481):117-20 PMID: 24284625
  13. EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.
    Stem Cell Reports. 2015 Feb 10;4(2):226-38 PMID: 25601206
  14. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions.
    Genome Biol. 2013 Apr 25;14(4):R36 PMID: 23618408
  15. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability.
    Mol Cell. 2011 Aug 5;43(3):327-39 PMID: 21723170
  16. The somatic genomic landscape of glioblastoma.
    Cell. 2013 Oct 10;155(2):462-77 PMID: 24120142
  17. Inactivation of the Fto gene protects from obesity.
    Nature. 2009 Apr 16;458(7240):894-8 PMID: 19234441
  18. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation.
    Nat Biotechnol. 2010 May;28(5):511-5 PMID: 20436464
  19. Malignant gliomas in adults.
    N Engl J Med. 2008 Jul 31;359(5):492-507 PMID: 18669428
  20. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR.
    Mol Cell. 2011 Aug 5;43(3):340-52 PMID: 21723171
  21. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation.
    Nat Chem Biol. 2014 Feb;10(2):93-5 PMID: 24316715
  22. Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22.
    Nat Cell Biol. 2016 Sep;18(9):954-66 PMID: 27501329
  23. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions.
    Nature. 2015 Feb 26;518(7540):560-4 PMID: 25719671
  24. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome.
    Nat Methods. 2016 Aug;13(8):692-8 PMID: 27376769
  25. FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells.
    Cancer Res. 2006 Apr 1;66(7):3593-602 PMID: 16585184
  26. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells.
    Nat Cell Biol. 2014 Feb;16(2):191-8 PMID: 24394384
  27. Coordination of m(6)A mRNA Methylation and Gene Transcription by ZFP217 Regulates Pluripotency and Reprogramming.
    Cell Stem Cell. 2015 Dec 3;17 (6):689-704 PMID: 26526723
  28. FoxM1 Promotes Stemness and Radio-Resistance of Glioblastoma by Regulating the Master Stem Cell Regulator Sox2.
    PLoS One. 2015 Oct 07;10 (10 ):e0137703 PMID: 26444992
  29. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.
    Cell Stem Cell. 2015 Mar 5;16(3):289-301 PMID: 25683224
  30. Dynamic m(6)A mRNA methylation directs translational control of heat shock response.
    Nature. 2015 Oct 22;526(7574):591-4 PMID: 26458103
  31. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq.
    Nature. 2012 Apr 29;485(7397):201-6 PMID: 22575960
  32. Mesenchymal differentiation mediated by NF-κB promotes radiation resistance in glioblastoma.
    Cancer Cell. 2013 Sep 9;24(3):331-46 PMID: 23993863
  33. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma.
    Cancer Cell. 2010 May 18;17(5):510-22 PMID: 20399149
  34. Hypoxia induces the breast cancer stem cell phenotype by HIF-dependent and ALKBH5-mediated m⁶A-demethylation of NANOG mRNA.
    Proc Natl Acad Sci U S A. 2016 Apr 5;113(14 ):E2047-56 PMID: 27001847
  35. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells.
    Proc Natl Acad Sci U S A. 1974 Oct;71(10):3971-5 PMID: 4372599
  36. FoxM1 Drives a Feed-Forward STAT3-Activation Signaling Loop That Promotes the Self-Renewal and Tumorigenicity of Glioblastoma Stem-like Cells.
    Cancer Res. 2015 Jun 1;75(11):2337-48 PMID: 25832656
  37. Cancer stem cells in glioblastoma.
    Genes Dev. 2015 Jun 15;29(12):1203-17 PMID: 26109046
  38. Formation of intracranial tumors by genetically modified human astrocytes defines four pathways critical in the development of human anaplastic astrocytoma.
    Cancer Res. 2001 Jul 1;61(13):4956-60 PMID: 11431323
  39. FoxM1 promotes β-catenin nuclear localization and controls Wnt target-gene expression and glioma tumorigenesis.
    Cancer Cell. 2011 Oct 18;20(4):427-42 PMID: 22014570
  40. MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells.
    Stem Cells. 2013 Jun;31(6):1051-63 PMID: 23404835
  41. FoxM1: a potential drug target for glioma.
    Future Oncol. 2012 Mar;8(3):223-6 PMID: 22409458
  42. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells.
    Mol Cell. 2016 May 5;62(3):335-45 PMID: 27117702
  43. Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation.
    Science. 2015 Feb 27;347(6225):1002-6 PMID: 25569111
  44. Total RNA sequencing reveals nascent transcription and widespread co-transcriptional splicing in the human brain.
    Nat Struct Mol Biol. 2011 Nov 06;18(12):1435-40 PMID: 22056773
  45. Heterogeneous nuclear RNA double-stranded regions probed in living HeLa cells by crosslinking with the psoralen derivative aminomethyltrioxsalen.
    Proc Natl Acad Sci U S A. 1979 Feb;76(2):755-9 PMID: 284397
  46. Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1α (HIF-1α).
    PLoS One. 2011 Jan 14;6(1):e16210 PMID: 21264265
  47. RNA-methylation-dependent RNA processing controls the speed of the circadian clock.
    Cell. 2013 Nov 7;155(4):793-806 PMID: 24209618
  48. Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing.
    Nat Protoc. 2013 Jan;8(1):176-89 PMID: 23288318
  49. FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.
    Cancer Cell. 2017 Jan 9;31(1):127-141 PMID: 28017614
  50. Antisense transcription in the mammalian transcriptome.
    Science. 2005 Sep 2;309(5740):1564-6 PMID: 16141073
Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2017.02.013
Email
suhuang@mdanderson.org
Published
2017-00-10
Epub
2017-00-23
Pages
591-606.e6
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC5427719
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R01 CA182684 · United States
NCI NIH HHS · R01 CA195651 · United States
NIGMS NIH HHS · R01 GM071440 · United States
NCI NIH HHS · R01 CA201327 · United States
NCI NIH HHS · R01 CA198090 · United States
NCI NIH HHS · R01 CA157933 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · R01 CA152309 · United States
NCI NIH HHS · P50 CA127001 · United States
Corrections
CommentIn
PMID: 28399407
External Links
PubMed source DOI: 10.1016/j.ccell.2017.02.013 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2