The interplay between m6A RNA methylation and noncoding RNA in cancer

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Abstract

N6-methyladenosine (m6A) methylation, one of the most common RNA modifications, has been reported to execute important functions that affect normal life activities and diseases. Most studies have suggested that m6A modification can affect the complexity of cancer progression by regulating biological functions related to cancer. M6A modification of noncoding RNAs regulates the cleavage, transport, stability, and degradation of noncoding RNAs themselves. It also regulates cell proliferation and metastasis, stem cell differentiation, and homeostasis in cancer by affecting the biological function of cells. Interestingly, noncoding RNAs also play significant roles in regulating these m6A modifications. Additionally, it is becoming increasingly clear that m6A and noncoding RNAs potentially contribute to the clinical application of cancer treatment. In this review, we summarize the effect of the interactions between m6A modifications and noncoding RNAs on the biological functions involved in cancer progression. In particular, we discuss the role of m6A and noncoding RNAs as possible potential biomarkers and therapeutic targets in the treatment of cancers.

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Most cited references 59

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Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex.

Jinju Han, Yoontae Lee, Kyu-Hyeon Yeom … (2006)

The Drosha-DGCR8 complex initiates microRNA maturation by precise cleavage of the stem loops that are embedded in primary transcripts (pri-miRNAs). Here we propose a model for this process that is based upon evidence from both computational and biochemical analyses. A typical metazoan pri-miRNA consists of a stem of approximately 33 bp, with a terminal loop and flanking segments. The terminal loop is unessential, whereas the flanking ssRNA segments are critical for processing. The cleavage site is determined mainly by the distance (approximately 11 bp) from the stem-ssRNA junction. Purified DGCR8, but not Drosha, interacts with pri-miRNAs both directly and specifically, and the flanking ssRNA segments are vital for this binding to occur. Thus, DGCR8 may function as the molecular anchor that measures the distance from the dsRNA-ssRNA junction. Our current study thus facilitates the prediction of novel microRNAs and will assist in the rational design of small hairpin RNAs for RNA interference.

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mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis

Junho Choe, Shuibin Lin, Wencai Zhang … (2018)

N 6-Methyladenosine (m6A) modification of messenger RNA (mRNA) is emerging as an important regulator of gene expression that impacts different developmental and biological processes, and altered m6A homeostasis is linked to cancer 1-5 . m6A is catalyzed by METTL3 and enriched in the 3’ untranslated region (3’ UTR) of a large subset of mRNAs at sites close to the stop codon 5 . METTL3 can promote translation but the mechanism and widespread relevance remain unknown 1 . Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon supporting a mRNA looping mechanism for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci found in close proximity to 5’ cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs, including Bromodomain-containing protein 4 (BRD4) that are also m6A-modified in human primary lung tumors. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes, and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mRNA looping mechanism of translation control and identify METTL3-eIF3h as a potential cancer therapeutic target.

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m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency.

Tong Chen, Ya-Juan Hao, Ying-ying Zhang … (2015)

N(6)-methyladenosine (m(6)A) has been recently identified as a conserved epitranscriptomic modification of eukaryotic mRNAs, but its features, regulatory mechanisms, and functions in cell reprogramming are largely unknown. Here, we report m(6)A modification profiles in the mRNA transcriptomes of four cell types with different degrees of pluripotency. Comparative analysis reveals several features of m(6)A, especially gene- and cell-type-specific m(6)A mRNA modifications. We also show that microRNAs (miRNAs) regulate m(6)A modification via a sequence pairing mechanism. Manipulation of miRNA expression or sequences alters m(6)A modification levels through modulating the binding of METTL3 methyltransferase to mRNAs containing miRNA targeting sites. Increased m(6)A abundance promotes the reprogramming of mouse embryonic fibroblasts (MEFs) to pluripotent stem cells; conversely, reduced m(6)A levels impede reprogramming. Our results therefore uncover a role for miRNAs in regulating m(6)A formation of mRNAs and provide a foundation for future functional studies of m(6)A modification in cell reprogramming.

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Author and article information

Contributors

Weitang Yuan: yuanweitang@zzu.edu.cn

Quancheng Kan: kanqc@zzu.edu.cn

Zhenqiang Sun:

ORCID: http://orcid.org/0000-0001-5926-2716

+86-037167967141 , zqsun82@csu.edu.cn

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 22 November 2019

Publication date PMC-release: 22 November 2019

Publication date Collection: 2019

Volume: 12

Electronic Location Identifier: 121

Affiliations

[1 ]GRID grid.412633.1, Department of Anorectal Surgery, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China

[2 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, Academy of Medical Sciences, , Zhengzhou University, ; Zhengzhou, 450052 Henan China

[3 ]GRID grid.412633.1, Department of Pharmacy, , The First Affiliated Hospital of Zhengzhou University, ; Zhengzhou, 450052 Henan China

Author information

Zhenqiang Sun http://orcid.org/0000-0001-5926-2716

Article

Publisher ID: 805

DOI: 10.1186/s13045-019-0805-7

PMC ID: 6874823

PubMed ID: 31757221

SO-VID: b8283d0a-60ea-4a2a-bb96-5b4aa31397c8

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 August 2019

Date accepted : 7 October 2019