m6A 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

Jin, Dayong; Guo, Jiwei; Wu, Yan; Du, Jing; Yang, Lijuan; Wang, Xiaohong; Di, Weihua; Hu, Baoguang; An, Jiajia; Kong, Lingqun; Pan, Lei; Su, Guoming

doi:10.1186/s13045-021-01048-8

Cited by 152 publications

(202 citation statements)

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“…It is reported that the methylation state of mRNA determines its expression level as the splicing, 9,38,39 translation, 40 transcription, 41 stability, 42 and export 43 of mRNA may be altered after the target genes are methylated or demethylated. 44 The study of m 6 A primarily reveals that the reduced global m 6 A methylation increases the lifetimes of nascent RNAs.…”

Section: Discussionmentioning

confidence: 99%

Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts

Zhuang

Yang

et al. 2020

FASEB j.

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Cardiac fibrosis is characterized by the activation of cardiac fibroblasts and accumulation of extracellular matrix. METTL3, a component of methyltransferase complex, participates in multiple biological processes associated with mammalian development and disease progression. However, the role of METTL3 in cardiac fibrosis is still unknown. We performed fibroblasts activation with TGF-β1 (20 ng/mL) in vitro and established in vivo mouse models with lentivirus to assess the effects of METTL3 on cardiac fibroblasts proliferation and collagen formation. Methylated RNA immunoprecipitation (MeRIP) was used to define the potential fibrosis-regulated gene. The expression level of METTL3 was increased in cardiac fibrotic tissue of mice with chronic myocardial infarction and cultured cardiac fibroblats (CFs) treated with TGF-β1. Enforced expression of METTL3 promoted proliferation and fibroblastto-myofibroblast transition and collagens accumulation, while silence of METTL3 did the opposite. Silence of METTL3 by lentivirus carrying METTL3 siRNA markedly alleviated cardiac fibrosis in MI mice. Transcriptome and N6-methyladenosine (m 6 A) profiling analyses revealed that the expression and m 6 A level of collagen-related genes were altered after silence of METTL3. METTL3-mediated m 6 A modification is critical for the development of cardiac fibrosis, providing a molecular target for manipulating fibrosis and the associated cardiac diseases.

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Section: Discussionmentioning

confidence: 99%

Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts

Zhuang

Yang

et al. 2020

FASEB j.

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“…The overexpression of METTL3 and its adverse prognostic impacts have also been reported in BLC, in which it promotes methylation of target mRNAs (e.g., AFF4, MYC, CDCP1, ITGA6) or miRNAs (i.e., pri-miR221/222) (Cheng et al, 2019a;Han et al, 2019b;Jin et al, 2019b;Yang et al, 2019a). Interestingly, the oncogenic function of METTL3 in NSCLC is complicated, where METTL3 could methylate YAP mRNA and recruit YTHDF1/3 and eIF3b to promote translation of YAP mRNA (Jin et al, 2019a), or could interact with eIF3h to promote translation of target mRNAs (e.g., BRD4) independently of its enzymatic activity (Choe et al, 2018;Lin et al, 2016). The enzyme activity-independent oncogenic role of METTL3 was also reported in ovarian cancer (OVC) (Hua et al, 2018).…”

Section: Aberrant M 6 a Regulation In Cancersmentioning

confidence: 93%

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

2020

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affects mRNA stability (stabilized by IGF2BP1/2/3 proteins and destabilized by YTHDF2/3 proteins), translation initiation, and translation elongation. m 6 A marks on lncRNAs play roles in RNA-RNA interaction, RNA-protein interaction, and chromatin remodeling. Antisense lncRNAs could modulate m 6 A abundance on the sense mRNA by recruiting m 6 A eraser (i.e., ALKBH5). Presence of m 6 A on pri-miRNA facilitates miRNA processing. In circRNAs, m 6 A could promote protein synthesis or inhibit circRNA immunity.

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“…More than 100 structurally distinct chemical modifications have been detected in RNAs [4,5], among these, N6-methyladnosine(m6A) modification represents the most prevailing chemical mark in eukaryotic mRNAs [6,7]. M6A modification is mainly mediated by the m6A methyltransferases (writers), including methyltransferase-like 14 (METTL14) [8], methyltransferase-like 3(METTL3) [9], vir-Like m6A methyltransferase associated (KIAA1429) [10] and Wilms tumor 1 associated protein (WTAP) [11], and can be removed by m6A demethylases (erasers) consists of alkylation repair homolog protein 5 (ALKBH5) [12] and fat-mass and obesity-associated protein (FTO) [13]. m6A modification exerts its effects on mRNAs via recruiting reader proteins, mainly including YTH domain-containing family protein 1/2/ 3(YTHDF1/2/3), insulin-like growth factor 2 mRNAbinding proteins 1/2/3(IGF2BP1/2/3) and heterogeneous nuclear ribonucleoprotein family (HNRNPA2B1, HNRNPC) [14,15].…”

Section: Introductionmentioning

confidence: 99%

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer

et al. 2020

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Background Colorectal cancer (CRC) is one of the leading causes of tumor-related death worldwide, and its main cause of death is distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, is involved in tumor progression via regulating RNA function. The goal of the study is to uncover the biological function and molecular mechanism of METTL14 in CRC. Methods Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were employed to detect METTL14 and SOX4 in CRC cell lines and tissues. The biological functions of METTL14 were demonstrated using in vitro and in vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic RNA sequencing (RNA-Seq), m6A-RNA immunoprecipitation sequencing (MeRIP-Seq), RNA immunoprecipitation and luciferase reporter assays were used to explore the mechanism of METTL14 action. Results METTL14 expression was significantly downregulated in CRC and decreased METTL14 was associated with poor overall survival (OS). Both the univariate and multivariate Cox regression analysis indicated that METTL14 was an independent prognostic factor in CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation of histone H3 lysine 4 tri-methylation(H3K4me3) in the promoter of METTL14 inhibited METTL14 transcription. Functionally, we verified that METTL14 inhibited CRC cells migration, invasion and metastasis through in vitro and in vivo assays, respectively. Furthermore, we identified SRY-related high-mobility-group box 4(SOX4) as a target of METTL14-mediated m6A modification. Knockdown of METTL14 markedly abolished SOX4 mRNA m6A modification and elevated SOX4 mRNA expression. We also revealed that METTL14-mediated SOX4 mRNA degradation relied on the YTHDF2-dependent pathway. Lastly, we demonstrated that METTL14 might inhibit CRC malignant process partly through SOX4-mediated EMT process and PI3K/Akt signals. Conclusions Decreased METTL14 facilitates tumor metastasis in CRC, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for CRC. Graphical abstract

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m6A 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

Cited by 152 publications

References 1 publication

Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts

Silencing of METTL3 attenuates cardiac fibrosis induced by myocardial infarction via inhibiting the activation of cardiac fibroblasts

m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer

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