m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

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

doi:10.1016/j.ccell.2017.02.013

Cited by 1,200 publications

(1,234 citation statements)

References 49 publications

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“…Here, we establish a novel link between TARBP2 intronic binding, m 6 A methylation, and controlled intron retention leading to transcript degradation in the nucleus. Although RNA methylation marks impact a variety of developmental and disease processes (Zhang et al, 2017a(Zhang et al, , 2017b (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”

Section: Discussionmentioning

confidence: 99%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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SUMMARYPost-transcriptional regulation of RNA stability is a key step in gene expression control. We describe a regulatory program, mediated by the double-stranded RNA binding protein TARBP2, that controls RNA stability in the nucleus. TARBP2 binding to pre-mRNAs results in increased intron retention, subsequently leading to targeted degradation of TARBP2-bound transcripts. This is mediated by TARBP2 recruitment of the m 6 A RNA methylation machinery to its target transcripts, where deposition of m 6 A marks influences the recruitment of splicing regulators, inhibiting efficient splicing. Interactions between TARBP2 and the nucleoprotein TPR then promote degradation of these TARBP2-bound transcripts by the nuclear exosome. Additionally, analysis of clinical gene expression datasets revealed a functional role for this TARBP2 pathway in lung cancer. Using xenograft mouse models, we find that TARBP2 impacts tumor growth in the lung, and that this function is dependent on TARBP2-mediated destabilization of ABCA3 and FOXN3. Finally, we establish the transcription factor ZNF143 as an upstream regulator of TARBP2 expression. RESEARCH HIGHLIGHTS• The RNA-binding protein TARBP2 controls the stability of its target transcripts in the nucleus• Nuclear TARBP2 recruits the methyltransferase complex to deposit m 6 A marks on its target transcripts • TARBP2 and m 6 A-mediated interactions with splicing and nuclear RNA surveillance complexes result in target transcript intron retention and decay.• Increased TARBP2 expression is associated with lung cancer and promotes lung cancer growth in vivo.• The transcription factor ZNF143 drives oncogenic TARBP2 upregulation in lung cancer.

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Section: Discussionmentioning

confidence: 99%

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Fish

Nguyen

Zhang

et al. 2018

Preprint

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“…Therefore, ZNF217 depletion leads to impaired hypoxia‐induced consistent enrichment of BCSCs with ALKBH5 deficiency 74. In terms of glioblastoma, inactivated ALKBH5 inhibited the proliferation and tumorigenesis of GSCs and impaired GSCs self‐renewal 75. It is widely accepted that FOXM1 plays a pivotal role in regulating GSCs proliferation and self‐renewal 76, 77.…”

Section: The Dual Role Of M6a Modification In Human Cancersmentioning

confidence: 99%

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

Wang

et al. 2018

J Cellular Molecular Medi

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As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.

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“…N 6 -methyladenosine (m 6 A) is one of the most common modification in mRNA, rRNA, tRNA, microRNA and long noncoding RNA (2,3). More recently, it has been reported that the m 6 A methylation plays important roles in the regulation of the circadian clock, meiosis, mRNA degradation and translation as well as microRNA processing (3–7), and moreover, dysregulation of this modification is linked with cancer (8) as well as neurogenesis, learning and memory (9). …”

Section: Introductionmentioning

confidence: 99%

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

Hou

Zhang

et al. 2018

Nucleic Acids Research

242

176

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The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1. SUMOylation of METTL3 does not alter its stability, localization and interaction with METTL14 and WTAP, but significantly represses its m6A methytransferase activity resulting in the decrease of m6A levels in mRNAs. Consistently with this, the abundance of m6A in mRNAs is increased with re-expression of the mutant METTL3-4KR compared to that of wild-type METTL3 in human non-small cell lung carcinoma (NSCLC) cell line H1299-shMETTL3, in which endogenous METTL3 was knockdown. The alternation of m6A in mRNAs and subsequently change of gene expression profiles, which are mediated by SUMOylation of METTL3, may directly influence the soft-agar colony formation and xenografted tumor growth of H1299 cells. Our results uncover an important mechanism for SUMOylation of METTL3 regulating its m6A RNA methyltransferase activity.

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m 6 A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program

Cited by 1,200 publications

References 49 publications

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

Nuclear TARBP2 drives oncogenic dysregulation of RNA splicing and decay

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

SUMOylation of the m6A-RNA methyltransferase METTL3 modulates its function

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