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

By Sicong Zhang, B. Zhao, Aidong Zhou, Kangyu Lin, Shaoping Zheng, Zhike Lu, Yaohui Chen, E. Sulman, K. Xie, O. Bögler and 3 more. Cancer Cell, 2017

1,279 citations recorded by the source corpus.

SUMMARY 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. Further, a long noncoding 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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/28d63b6217ae3cb398d568b7c761e81a3a568956

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Citations in the corpus

The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells (2017, neutral): “Unlike in glioblastoma where m 6 A depletion promotes tumorigenesis 29, 30 , we find that METTL3 and m 6 A maintains the undifferentiated leukemic phenotype.”
RNA modifications modulate gene expression during development (2018, positive): “Similarly, overexpression of ALKBH5 or downregulation of METTL3 or METTL14 promotes the tumorigenicity of glioblastoma cells through stabilization of pro-proliferative transcripts like FOXM1 ( 63, 64 ).”
The potential role of RNA N6-methyladenosine in Cancer progression (2020, background): “Depleting ALKBH5 and FOXM1-AS abolished the tumorigenicity of GSCs through the FOXM1 axis [77].”
Rethinking m6A Readers, Writers, and Erasers (2017, background): “Nevertheless, Zhang et al. (2017) identified a specific m6A in FOXMI mRNA that appears to be regulated by ALKBH5.”
Where, when and how: context-dependent functions of RNA methylation writers, readers, and erasers (2019, background): “…hypoxia induced HIF-dependent breast cancer stem cell phenotype (Zhang et al., 2016), regulating glioblastoma proliferation and tumorigenesis through the ALKBH5-FOXM1 pathway (Zhang et al., 2017), and modulating splicing and stability of long 3’ UTR mRNAs in male germ cells (Tang et al., 2018).”
Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism (2018, background): “A recent study revealed that overexpression of ALKBH5 is required for the proliferation and tumorigenesis of glioblastoma stem cells and predicts poor patient survival.(97) m(6)A: Dynamics and RNA metabolism Y.”
Functions of N6-methyladenosine and its role in cancer (2019, background): “Nuclear lncRNA FOXM1-AS promotes the association between ALKBH5 with FOXM1 nascent RNA, leading to enhanced FOXM1 expression and GSC pathogenesis [21].”
RNA N6-methyladenosine modification in cancers: current status and perspectives (2018, background): “Thus, FTO likely also plays a critical oncogenic role in self-renewal of GSCs and is required for the development of GBM.”