title: m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells.
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.
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Chemistry and Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Hailing
authors.initials: H
authors.lastname: Shi
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Qiuhao
authors.initials: Q
authors.lastname: Qu
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Sun
authors.affiliation: Diabetes and Metabolism Research Institute at City of Hope, Duarte, CA 91010, USA.
authors.forename: Guihua
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Zhike
authors.initials: Z
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Cai-Guang
authors.initials: CG
authors.lastname: Yang
authors.affiliation: Diabetes and Metabolism Research Institute at City of Hope, Duarte, CA 91010, USA.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.affiliation: Department of Chemistry and Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: yshi@coh.org.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000066673:Cell Self Renewal / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D008469:Meclofenamic Acid / Q000494:pharmacology; D008745:Methylation; D008780:Methyltransferases / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012313:RNA / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D008469:Meclofenamic Acid; D012313:RNA; C010223:N-methyladenosine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; C587355:METTL14 protein, human; D008780:Methyltransferases; C468275:METTL3 protein, human; D000241:Adenosine
keywords: FTO inhibitor; METTL14; METTL3; glioblastoma stem cells; m(6)A modification