39
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      m 6A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          METTL3 is an RNA methyltransferase that mediates m 6A modification and is implicated in mRNA biogenesis, decay, and translation. However, the biomechanism through which METTL3 regulates MALAT1-miR-1914-3p-YAP axis activity to induce NSCLC drug resistance and metastasis is not very clear.

          Methods

          The expression of mRNA was analyzed by qPCR assays. Protein levels were analyzed by western blotting and immunofluorescent staining. Cellular proliferation was detected by CCK8 assays. Cell migration and invasion were analyzed by wound healing and transwell assays, respectively. Promoter activities and gene transcription were analyzed by luciferase reporter assays. Finally, m 6A modification was analyzed by MeRIP.

          Results

          METTL3 increased the m 6A modification of YAP. METTL3, YTHDF3, YTHDF1, and eIF3b directly promoted YAP translation through an interaction with the translation initiation machinery. Moreover, the RNA level of MALAT1 was increased due to a higher level of m 6A modification mediated by METTL3. Meanwhile, the stability of MALAT1 was increased by METTL3/YTHDF3 complex. Additionally, MALAT1 functions as a competing endogenous RNA that sponges miR-1914-3p to promote the invasion and metastasis of NSCLC via YAP. Furthermore, the reduction of YAP m 6A modification by METTL3 knockdown inhibits tumor growth and enhances sensitivity to DDP in vivo.

          Conclusion

          Results indicated that the m 6A mRNA methylation initiated by METTL3 promotes YAP mRNA translation via recruiting YTHDF1/3 and eIF3b to the translation initiation complex and increases YAP mRNA stability through regulating the MALAT1-miR-1914-3p-YAP axis. The increased YAP expression and activity induce NSCLC drug resistance and metastasis.

          Related collections

          Most cited references15

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

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

          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.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            YAP/TAZ upstream signals and downstream responses

            Cell behavior is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP/TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behavior, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP/TAZ activation that is instrumental for multiple diseases, including cancer.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis

              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.
                Bookmark

                Author and article information

                Contributors
                guojiwei0510@163.com
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                9 December 2019
                9 December 2019
                2019
                : 12
                : 135
                Affiliations
                [1 ]GRID grid.452240.5, Clinical Medical Laboratory, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [2 ]GRID grid.452240.5, Cancer research institute, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [3 ]GRID grid.452240.5, Department of Thyroid and Breast Surgery, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [4 ]GRID grid.452240.5, Department of Pain, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [5 ]GRID grid.452240.5, Department of Gastrointestinal Surgery, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [6 ]GRID grid.452240.5, Department of Clinical Laboratory, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [7 ]GRID grid.452240.5, Department of Hepatobiliary Surgery, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [8 ]GRID grid.452240.5, Department of Respiratory and Critical Care Medicine, , Binzhou Medical University Hospital, ; Binzhou, 256603 People’s Republic of China
                [9 ]Department of Nursing, Binzhou Polytechnic University, Binzhou, 256603 People’s Republic of China
                Author information
                http://orcid.org/0000-0003-1636-6499
                Article
                830
                10.1186/s13045-019-0830-6
                6902496
                31818312
                166c61d0-7ef4-4eee-9b5b-3f61494e37f7
                © The Author(s). 2019

                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
                : 10 October 2019
                : 13 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31801085
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100007129, Natural Science Foundation of Shandong Province;
                Award ID: ZR2018QH004
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100014103, Key Technology Research and Development Program of Shandong;
                Award ID: 2019GSF108174
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                m6a modification,mettl3,ythdf1/3,eif3b,malat1,mir-1914-3p,yap
                Oncology & Radiotherapy
                m6a modification, mettl3, ythdf1/3, eif3b, malat1, mir-1914-3p, yap

                Comments

                Comment on this article