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      N 6-methyladenosine (m 6A) RNA modification in gastrointestinal tract cancers: roles, mechanisms, and applications

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          Abstract

          Analogous to DNA methylation and histone modification, RNA modification, as another epigenetic layer, plays an important role in many diseases, especially in tumours. As the most common form of RNA modification, m 6A methylation has attracted increasing research interest in recent years. m 6A is catalysed by RNA methyltransferases METTL3, METTL14 and WTAP (writers), m 6A is removed by the demethylases FTO and ALKBH5 (erasers) and interacts with m6A-binding proteins, such as YT521-B homology (YTH) domain-containing proteins. This article reviews recent studies on methylation modification of m 6A in gastrointestinal tract cancers.

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          METTL3 facilitates tumor progression via an m 6 A-IGF2BP2-dependent mechanism in colorectal carcinoma

          Ting Li, Pei-Shan Hu, Zhixiang Zuo … (2019)
          Background Colorectal carcinoma (CRC) is one of the most common malignant tumors, and its main cause of death is tumor metastasis. RNA N6-methyladenosine (m6A) is an emerging regulatory mechanism for gene expression and methyltransferase-like 3 (METTL3) participates in tumor progression in several cancer types. However, its role in CRC remains unexplored. Methods Western blot, quantitative real-time PCR (RT-qPCR) and immunohistochemical (IHC) were used to detect METTL3 expression in cell lines and patient tissues. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and transcriptomic RNA sequencing (RNA-seq) were used to screen the target genes of METTL3. The biological functions of METTL3 were investigated in vitro and in vivo. RNA pull-down and RNA immunoprecipitation assays were conducted to explore the specific binding of target genes. RNA stability assay was used to detect the half-lives of the downstream genes of METTL3. Results Using TCGA database, higher METTL3 expression was found in CRC metastatic tissues and was associated with a poor prognosis. MeRIP-seq revealed that SRY (sex determining region Y)-box 2 (SOX2) was the downstream gene of METTL3. METTL3 knockdown in CRC cells drastically inhibited cell self-renewal, stem cell frequency and migration in vitro and suppressed CRC tumorigenesis and metastasis in both cell-based models and PDX models. Mechanistically, methylated SOX2 transcripts, specifically the coding sequence (CDS) regions, were subsequently recognized by the specific m6A “reader”, insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2), to prevent SOX2 mRNA degradation. Further, SOX2 expression positively correlated with METTL3 and IGF2BP2 in CRC tissues. The combined IHC panel, including “writer”, “reader”, and “target”, exhibited a better prognostic value for CRC patients than any of these components individually. Conclusions Overall, our study revealed that METTL3, acting as an oncogene, maintained SOX2 expression through an m6A-IGF2BP2-dependent mechanism in CRC cells, and indicated a potential biomarker panel for prognostic prediction in CRC. Electronic supplementary material The online version of this article (10.1186/s12943-019-1038-7) contains supplementary material, which is available to authorized users.
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            Mettl1/Wdr4-Mediated m7G tRNA Methylome Is Required for Normal mRNA Translation and Embryonic Stem Cell Self-Renewal and Differentiation

            Jack W. Szostak, Richard Gregory, Shuibin Lin … (2018)
            tRNAs are subject to numerous modifications including methylation. Mutations in the human N 7 -methylguanosine (m 7 G) methyltransferase complex METTL1/WDR4 cause primordial dwarfism and brain malformation yet the molecular and cellular function in mammals is not well understood. We developed m 7 G methylated tRNA immunoprecipitation sequencing (MeRIP-Seq) and tRNA reduction and cleavage sequencing (TRAC-Seq) to reveal the m 7 G tRNA methylome in mouse embryonic stem cells (mESCs). A subset of 22 tRNAs are modified at a ‘RAGGU’ motif within the variable loop. We observe increased ribosome occupancy at the corresponding codons in Mettl1 knockout mESCs implying widespread effects on tRNA function, ribosome pausing, and mRNA translation. Translation of cell cycle genes and those associated with brain abnormalities is particularly affected. Mettl1 or Wdr4 knockout mESCs display defective self-renewal and neural differentiation. Our study uncovers the complexity of the mammalian m 7 G tRNA methylome and highlights its essential role in ESCs with links to human disease. Lin and Liu et al. developed two independent methods, MeRIP-Seq and TRAC-Seq, to profile the m 7 G tRNA methylome in mouse ESCs and revealed that Mettl1/Wdr4- mediated m 7 G tRNA methylome is required for normal mRNA translation and ESC self- renewal and differentiation.
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              The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells

              Jun Koseki, Masayasu Toratani, Taroh Satoh … (2017)
              N6-methyladenosine (m6A) is the most abundant epitranscriptome modification in mammalian mRNA. Recent years have seen substantial progress in m6A epitranscriptomics, indicating its crucial roles in the initiation and progression of cancer through regulation of RNA stabilities, mRNA splicing, microRNA processing and mRNA translation. However, by what means m6A is dynamically regulated or written by enzymatic components represented by methyltransferase-like 3 (METTL3) and how m6A is significant for each of the numerous genes remain unclear. We focused on METTL3 in pancreatic cancer, the prognosis of which is not satisfactory despite the development of multidisciplinary therapies. We established METTL3-knockdown pancreatic cancer cell line using short hairpin RNA. Although morphologic and proliferative changes were unaffected, METTL3-depleted cells showed higher sensitivity to anticancer reagents such as gemcitabine, 5-fluorouracil, cisplatin and irradiation. Our data suggest that METTL3 is a potent target for enhancing therapeutic efficacy in patients with pancreatic cancer. In addition, we performed cDNA expression analysis followed by gene ontology and protein-protein interaction analysis using the Database for Annotation, Visualization, and Integrated Discovery and Search Tool for the Retrieval of Interacting Genes/Proteins databases, respectively. The results demonstrate that METTL3 was associated with mitogen-activated protein kinase cascades, ubiquitin-dependent process and RNA splicing and regulation of cellular process, suggesting functional roles and targets of METTL3.
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                Author and article information

                Contributors
                Zhen-jun Gao: gaozhenjun@sina.com
                Heng Zhang: 1243487570@qq.com
                Yu Fan: yuf36@sina.com
                Journal
                Journal ID (nlm-ta): Mol Cancer
                Journal ID (iso-abbrev): Mol. Cancer
                Title: Molecular Cancer
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1476-4598
                Publication date (Electronic): 7 December 2019
                Publication date PMC-release: 7 December 2019
                Publication date Collection: 2019
                Volume: 18
                Electronic Location Identifier: 178
                Affiliations
                [1 ]GRID grid.452247.2, Cancer Institue, Affiliated People’s Hospital of Jiangsu University, ; Zhenjiang, Jiangsu Province, People’s Republic of China
                [2 ]ISNI 0000 0004 1799 0784, GRID grid.412676.0, Digestive Department, , Suqian Branch Hospital of Jiangsu Province Hospital, ; Jiangsu Suqian, People’s Republic of China
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Digestive Department, Qingpu Branch Hospital of Affiliated Zhongshan Hospital, , Fudan University, ; Shanghai, People’s Republic of China
                [4 ]ISNI 0000 0004 1761 0489, GRID grid.263826.b, Department of General Surgery, Nanjing Lishui District People’s Hospital, Zhongda Hospital Lishui Branch, , Southeast University, ; Nanjing, China
                Article
                Publisher ID: 1099
                DOI: 10.1186/s12943-019-1099-7
                PMC ID: 6898962
                PubMed ID: 31810483
                SO-VID: bfcf06d4-20d2-4bc7-8539-1b15ca8f2909
                Copyright © © The Author(s). 2019
                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 : 15 July 2019
                Date accepted : 8 November 2019
                Funding
                Funded by: Jiangsu Provincial Key Research and Development Special Fund
                Award ID: BE2015666
                Award Recipient :
                Funded by: Jiangsu Innovative team leading talent fund
                Award ID: CXTDC2016006
                Award Recipient :
                Funded by: Jiangsu Natural Science Foundation
                Award ID: BK20171304
                Award Recipient :
                Funded by: Jiangsu six high peak talent fund
                Award ID: WSW-205
                Award Recipient :
                Funded by: Jiangsu 333 talent fund
                Award ID: BRA2016140
                Award Recipient :
                Funded by: Suqian Science and Technology Support Project
                Award ID: S201522
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2019

                ScienceOpen disciplines: Oncology & Radiotherapy
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy

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