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

Sicong Zhang; Boxuan Simen Zhao; Aidong Zhou; Kangyu Lin; Shaoping Zheng; Zhike Lu; Yaohui Chen; Erik P. Sulman; Keping Xie; Oliver Bögler; Sadhan Majumder; Chuan He; Suyun Huang

doi:10.1016/j.ccell.2017.02.013

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

Sicong Zhang, Boxuan Simen Zhao, Aidong Zhou, Kangyu Lin, Shaoping Zheng, Zhike Lu, Yaohui Chen, Erik P. Sulman, Keping Xie, Oliver Bögler, Sadhan Majumder, Chuan He, Suyun Huang

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	591-606.e6
Journal	Cancer Cell
Volume	31
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2017.02.013
State	Published - Apr 10 2017
Externally published	Yes

Keywords

ALKBH5
FOXM1
glioblastoma
mA modification

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Online availability

10.1016/j.ccell.2017.02.013

Library availability

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Cite this

@article{59043c505ff346cfac176399ca80aa25,

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

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, mA modification",

author = "Sicong Zhang and Zhao, {Boxuan Simen} and Aidong Zhou and Kangyu Lin and Shaoping Zheng and Zhike Lu and Yaohui Chen and Sulman, {Erik P.} and Keping Xie and Oliver B{\"o}gler and Sadhan Majumder and Chuan He and Suyun Huang",

note = "Funding Information: We thank Drs. R. Behringer and Z. Fan for scientific suggestions, and L. Ma for assistance with revision. We thank Joseph A. Munch for language editing. This work was supported in part by US NIH grants R01CA157933, R01CA182684, R01CA201327, R01CA152309, CA16672, and GM071440. C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). B.S.Z. is an HHMI International Student Research fellow. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

year = "2017",

month = apr,

day = "10",

doi = "10.1016/j.ccell.2017.02.013",

language = "English (US)",

volume = "31",

pages = "591--606.e6",

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T1 - m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

AU - Zhang, Sicong

AU - Zhao, Boxuan Simen

AU - Zhou, Aidong

AU - Lin, Kangyu

AU - Zheng, Shaoping

AU - Lu, Zhike

AU - Chen, Yaohui

AU - Sulman, Erik P.

AU - Xie, Keping

AU - Bögler, Oliver

AU - Majumder, Sadhan

AU - He, Chuan

AU - Huang, Suyun

N1 - Funding Information: We thank Drs. R. Behringer and Z. Fan for scientific suggestions, and L. Ma for assistance with revision. We thank Joseph A. Munch for language editing. This work was supported in part by US NIH grants R01CA157933, R01CA182684, R01CA201327, R01CA152309, CA16672, and GM071440. C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). B.S.Z. is an HHMI International Student Research fellow. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/4/10

Y1 - 2017/4/10

N2 - 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.

AB - 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.

KW - ALKBH5

KW - FOXM1

KW - glioblastoma

KW - mA modification

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JF - Cancer Cell

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