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      The m6A methyltransferase METTL3 controls epithelial-mesenchymal transition, migration and invasion of breast cancer through the MALAT1/miR-26b/HMGA2 axis

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          Abstract

          Background

          Previous studies have revealed the key functions of N6-methyladenosine (m6A) modification in breast cancer (BC). MALAT1 as a highly m6A modified lncRNA associated with cancer development and metastasis, but the functional relevance of m6A methyltransferase and MALAT1 in BC is still unknown. Here, our study investigated the effects of the novel m6A methyltransferase METTL3 on epithelial-mesenchymal transition (EMT) in BC via the MALAT1/miR-26b/HMGA2 axis.

          Methods

          Firstly, we collected clinical BC samples and cultured BC cells, and detected mRNA and protein levels in the human samples and human cell lines by RT-qPCR and Western blot, respectively. Then, the binding of MALAT1 and miR-26b and the targeting relationship between miR-26b and HMGA2 were examined by dual-luciferase assay. Moreover, the binding of MALAT1 and miR-26b was tested by RNA pull down and RNA immunoprecipitation (RIP) assays. Methylated-RNA immunoprecipitation (Me-RIP) was used to detect the m6A modification level of MALAT1. The interaction of METTL3 and MALAT1 was detected by photoactivatable ribonucleoside-crosslinking immunoprecipitation (PAR-CLIP). Finally, effects on invasion and migration were detected by Transwell.

          Results

          In BC, the level of miR-26b was consistently low, while the levels of METTL3, MALAT1 and HMGA2 were high. Further experiments showed that METTL3 up-regulated MALAT1 expression by modulating the m6A modification of MALAT1, and that MALAT1 could promote the expression of HMGA2 by sponging miR-26b. In BC cells, we found that silencing METTL3 could inhibit EMT and tumor cell invasion by suppressing MALAT1. Furthermore, MALAT1 mediated miR-26b to target HMGA2 and promote EMT, migration, and invasion. In summary, METTL3 promoted tumorigenesis of BC via the MALAT1/miR-26b/HMGA2 axis.

          Conclusions

          Silencing METTL3 down-regulate MALAT1 and HMGA2 by sponging miR-26b, and finally inhibit EMT, migration and invasion in BC, providing a theoretical basis for clinical treatment of BC.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12935-021-02113-5.

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          Most cited references38

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          The basics of epithelial-mesenchymal transition.

          The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.
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            EMT: 2016.

            The significant parallels between cell plasticity during embryonic development and carcinoma progression have helped us understand the importance of the epithelial-mesenchymal transition (EMT) in human disease. Our expanding knowledge of EMT has led to a clarification of the EMT program as a set of multiple and dynamic transitional states between the epithelial and mesenchymal phenotypes, as opposed to a process involving a single binary decision. EMT and its intermediate states have recently been identified as crucial drivers of organ fibrosis and tumor progression, although there is some need for caution when interpreting its contribution to metastatic colonization. Here, we discuss the current state-of-the-art and latest findings regarding the concept of cellular plasticity and heterogeneity in EMT. We raise some of the questions pending and identify the challenges faced in this fast-moving field.
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              Dynamic RNA Modifications in Gene Expression Regulation

              Over 100 types of chemical modifications have been identified in cellular RNAs. While the 5' cap modification and the poly(A) tail of eukaryotic mRNA play key roles in regulation, internal modifications are gaining attention for their roles in mRNA metabolism. The most abundant internal mRNA modification is N6-methyladenosine (m6A), and identification of proteins that install, recognize, and remove this and other marks have revealed roles for mRNA modification in nearly every aspect of the mRNA life cycle, as well as in various cellular, developmental, and disease processes. Abundant noncoding RNAs such as tRNAs, rRNAs, and spliceosomal RNAs are also heavily modified and depend on the modifications for their biogenesis and function. Our understanding of the biological contributions of these different chemical modifications is beginning to take shape, but it's clear that in both coding and noncoding RNAs, dynamic modifications represent a new layer of control of genetic information.
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                Author and article information

                Contributors
                ldyy_zhaochp@lzu.edu.cn
                lingxiaolinglzu@126.com
                xiayunxialzu@126.com
                yanbingxuelzu@126.com
                guanql@lzu.edu.cn
                Journal
                Cancer Cell Int
                Cancer Cell Int
                Cancer Cell International
                BioMed Central (London )
                1475-2867
                21 August 2021
                21 August 2021
                2021
                : 21
                : 441
                Affiliations
                [1 ]GRID grid.412643.6, Department of Medical Oncology, , The First Hospital of Lanzhou University, ; 730000 Lanzhou, People’s Republic of China
                [2 ]GRID grid.412643.6, The First School of Clinical Medicine, , The First Hospital of Lanzhou University, ; 730000 Lanzhou, People’s Republic of China
                [3 ]GRID grid.412643.6, Department of Oncology Surgery, , The First Hospital of Lanzhou University, ; No. 1, Western Donggang Road, Chengguan District, Gansu 730000 Lanzhou, People’s Republic of China
                Author information
                http://orcid.org/0000-0001-8800-7570
                Article
                2113
                10.1186/s12935-021-02113-5
                8380348
                34419065
                6808e66e-9cec-4156-b372-7272b428007b
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data.

                History
                : 12 October 2020
                : 24 July 2021
                Categories
                Primary Research
                Custom metadata
                © The Author(s) 2021

                Oncology & Radiotherapy
                breast cancer,mettl3,malat1,mir-26b,epithelial-mesenchymal transition
                Oncology & Radiotherapy
                breast cancer, mettl3, malat1, mir-26b, epithelial-mesenchymal transition

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