bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–11–07
twelve papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. N6-methyladenosine modification of CDH1 mRNA promotes PM2.5-induced pulmonary fibrosis via mediating epithelial mesenchymal transition.
  2. Identification of IGF2BP3 as an Adverse Prognostic Biomarker of Gliomas.
  3. N6-methyladenosine regulates ATM expression and downstream signaling.
  4. Involvement of METTL3/m6Adenosine and TGFβ/Smad3 signaling on Tenon's fibroblasts and in a rabbit model of glaucoma surgery.
  5. Knockdown of METTL14 suppresses the malignant progression of non-small cell lung cancer by reducing Twist expression.
  6. The RNA N6 -methyladenosine modulator HNRNPA2B1 is involved in the development of non-small cell lung cancer.
  7. Identification and Validation of m6A-Related lncRNA Signature as Potential Predictive Biomarkers in Breast Cancer.
  8. N6-Methyladenosine-regulated LINC00675 Suppress the Proliferation, Migration and Invasion of Breast Cancer cells via Inhibiting miR-513b-5p.
  9. FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner.
  10. N6-Methyladenosine Methylomic Landscape of Lung Tissues in Murine Acute Allergic Asthma.
  11. Comprehensive analysis of N6 -methyladenosine-related long non-coding RNAs for prognosis prediction in liver hepatocellular carcinoma.
  12. Systematic detection of m6A-modified transcripts at single-molecule and single-cell resolution.
  1. Toxicol Sci. 2021 Nov 04. pii: kfab133. [Epub ahead of print]
    N6-methyladenosine modification of CDH1 mRNA promotes PM2.5-induced pulmonary fibrosis via mediating epithelial mesenchymal transition.
    Jie Ning, Hairong Du, Yaling Zhang, Qingping Liu, Tao Jiang, Yaxian Pang, Xiaochen Tian, Liqun Yan, Yujie Niu, Rong Zhang.
      The association between ambient airborne fine particulate matter (PM2.5) exposure and respiratory diseases has been investigated in epidemiological studies. To explore the potential mechanism of PM2.5-induced pulmonary fibrosis, sixty mice were divided into 3 groups to expose to different levels of PM2.5 for 8 and 16 weeks: filtered air (FA), unfiltered air (UA) and concentrated PM2.5 air (CA), respectively. BEAS-2B cells were treated with 0, 25, 50 and 100 μg/ml PM2.5 for 24 h. The biomarkers of pulmonary fibrosis, epithelial-mesenchymal transition (EMT), N6-methyladenosine (m6A) modification and metabolism of mRNAs were detected to characterize the effect of PM2.5 exposure. The results illustrated that PM2.5 exposure induced pathological alteration and pulmonary fibrosis in mice. The expression of E-cadherin (E-cad) was decreased whereas vimentin and N-cadherin (N-cad) expression were increased in a dose- and time-dependent manner after PM2.5 exposure. Mechanistically, PM2.5 exposure increased the levels of METTL3-mediated m6A modification of CDH1 mRNA. As a target gene of miR-494-3p, YTHDF2 was up-regulated by miR-494-3p down-regulation and then recognized m6A-modified CDH1 mRNA to inhibit the E-cad expression, consequently induced the EMT progression after PM2.5 exposure. Our study indicated that PM2.5 exposure triggered EMT progression to promote the pulmonary fibrosis via miR-494-3p/YTHDF2 recognized and METTL3 mediated m6A modification.
    Keywords:  METTL3; PM2.5; YTHDF2; epithelial-mesenchymal transition; m6A RNA methylation; pulmonary fibrosis
    DOI:  https://doi.org/10.1093/toxsci/kfab133
  2. Front Genet. 2021 ;12 743738
    Identification of IGF2BP3 as an Adverse Prognostic Biomarker of Gliomas.
    Chao Sun, Xin Zheng, Yingxin Sun, Ju Yu, Minfeng Sheng, Suji Yan, Qing Zhu, Qing Lan.
      N6-methyladenosine (m6A) RNA modification can alter gene expression and function by regulating RNA splicing, stability, translocation, and translation. It is involved in various types of cancer. However, its role in gliomas is not well known. This study aimed to determine the prognostic value of the m6A RNA methylation regulator in gliomas and investigate the underlying mechanisms of the aberrant expression of m6A-related genes.mRNA expression profiles and clinical information of 448 glioma samples were obtained from The Cancer Genome Atlas and cBioportal. The expression of m6A-related genes in normal controls and low-grade glioma and glioblastoma was obtained from Gene Expression Profiling Interactive Analysis. Further, m6A-related gene expression and its relationship with prognosis were obtained through The Chinese Glioma Genome Atlas (CGGA). Multivariate Cox regression analyses were performed, and a nomogram was built with potential risk factors based on a multivariate Cox analysis to predict survival probability. Online tools such as Gene Set Enrichment Analysis, STRING, Cytoscape, and Molecular Complex Detection were applied for bioinformatics analysis and to investigate the underlying mechanisms of the aberrant expression of m6A-related genes. The multivariate Cox regression analysis found that higher expression levels of YTHDC2 and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3, also called IMP3) were independent negative and positive prognostic factors for overall survival (OS), respectively. Data from the CGGA database showed that IGF2BP3 expression increased when the tumor grade increased. Receiver operating characteristic (ROC) curve was used to evaluate the predictive specificity and sensitivity. The area under the ROC curve indicated that the OS prediction was 0.92 (1-year) and 0.917 (3-years), indicating that m6A-related genes could predict patient survival. In addition, IGF2BP3 was closely related to the shorter survival period of patients. Copy number variation and DNA methylation, but not somatic mutations, might contribute to the abnormal upregulation of IGF2BP3 in gliomas. Significantly altered genes were identified, and the protein-protein interaction network was constructed. Based on the data presented, our study identified several m6A-related genes, especially IGF2BP3, that could be potential prognostic biomarkers of gliomas. The study unveiled the potential regulatory mechanism of IGF2BP3 in gliomas.
    Keywords:  IGF2BP3; M6A RNA methylation; glioma bioinformatics analysis; post-transcriptional modification; prognosis
    DOI:  https://doi.org/10.3389/fgene.2021.743738
  3. J Cancer. 2021 ;12(23): 7041-7051
    N6-methyladenosine regulates ATM expression and downstream signaling.
    Xiaoyue Zhang, Peishan Liu, Xiang Zheng, Jia Wang, Qiu Peng, Zhengshuo Li, Lingyu Wei, Can Liu, Yangge Wu, Yuqing Wen, Qun Yan, Jian Ma.
      N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNAs, which plays an important role in regulating multiple biological processes. ATM is a major protein kinase that regulates the DNA damage response. Here, we identified that ATM is a m6A-modificated gene. METTL3 (a m6A "writer") and FTO (a m6A "eraser") oppositely regulated ATM expression and its downstream signaling. Mechanically, m6A "readers" YTHDFs and eIF3A suppressed ATM expression in the post-transcriptional levels. We also revealed the oncogenic potential of METTL3 and YTHDF1 related to ATM modulation. This is the first report that ATM, a master in the DNA damage response, is modified by m6A epigenetic modification, and METTL3 disrupts the ATM stability via m6A modification, thereby affecting the DNA-damage response.
    Keywords:  ATM; DNA damage response; METTL3; YTHDF1; m6A modification
    DOI:  https://doi.org/10.7150/jca.64061
  4. J Mol Histol. 2021 Nov 02.
    Involvement of METTL3/m6Adenosine and TGFβ/Smad3 signaling on Tenon's fibroblasts and in a rabbit model of glaucoma surgery.
    Yan Liu, Chao Gu, Xiabin Li, Tingwei Wang, Ling Yu.
      Glaucoma filtration surgery (GFS) is a classic operation for the treatment of glaucoma, which is the second leading cause of blindness, and scar formation caused by excessive human Tenon's capsule fibroblasts (HTFs) activation is responsible for surgery failure. However, the mechanism underlying excessive HTFs activation is largely unknown. Studies have revealed that N6-methyladenosine (m6A), which is one of the most common posttranscriptional modifications, plays an important role in multiple types of cellular processes. First, we isolated and identified primary HTFs and found that transforming growth factor-β1 (TGF-β1) enhanced cell viability and promoted cell proliferation and extracellular matrix (ECM) deposition in HTFs. We subsequently found that TGF-β1 elevated the quantity of m6A and promoted the expression of m6A "writers", in the process from DNA to RNA, adenylate was methylated at the sixth N position by methylases methyltransferase-like 3 (METTL3). Furthermore, we demonstrated that METTL3 repression inhibited the promotion of cell viability, proliferation and ECM deposition in HTFs treated with TGF-β1. We then illustrated that increased METTL3 played a role by promoting Smad3 in TGF-β1-induced HTFs. We subsequently demonstrated that the METTL3/Smad3 regulatory axis was aberrantly expressed in the rabbit model of GFS. Thus, our study reveals that METTL3 indeed plays a role in modulating Smad3 in TGF-β1-induced HTFs and further provides novel theoretical strategies based on METTL3 for the inhibition of scar formation after GFS.
    Keywords:  Glaucoma filtration surgery; Human Tenon’s capsule fibroblasts; N6-methyladenosine; Smad3; Transforming growth factor-β1
    DOI:  https://doi.org/10.1007/s10735-021-10028-8
  5. Oncol Lett. 2021 Dec;22(6): 847
    Knockdown of METTL14 suppresses the malignant progression of non-small cell lung cancer by reducing Twist expression.
    Fang Yang, Wei-Qi Yuan, Juan Li, Yi-Qin Luo.
      Non-small cell lung cancer (NSCLC) is one of the most malignant cancer types. N6-methyladenosine (m6A), an abundant eukaryotic mRNA modification, has been observed in multiple diseases, particularly cancer. Methyltransferase-like 14 (METTL14) is a central component of the m6A methyltransferase complex and has been reported to promote tumor development in several cancer types. The present study aimed to investigate the role of METTL14 in NSCLC. Relevant clinical and mRNA sequencing data for m6A-related genes were downloaded from The Cancer Genome Atlas database. R software was used to evaluate the expression of m6A regulators in NSCLC. The biological functions of METTL14 were evaluated using Cell Counting Kit-8, colony formation, Transwell migration and western blot analyses. The results demonstrated that METTL14 expression was upregulated in NSCLC tissues and cell lines, and its expression was high in cancer tissues from patients with NSCLC with all four stages (I, II, III and IV) of disease. METTL14 downregulation inhibited cell proliferation and migration in A549 and SK-MES-1 lung cancer cell lines. Knockdown of METTL14 in lung cancer cell lines increased E-cadherin expression and suppressed N-cadherin expression. Furthermore, METTL14 downregulation reduced the expression levels of the transcription factor Twist and the p-AKT/AKT ratio. In conclusion, the present findings revealed that silencing of METTL14 suppressed NSCLC malignancy by inhibiting Twist-mediated activation of AKT signaling. These data suggest that METTL14 may be a potential therapeutic target for NSCLC.
    Keywords:  Twist; epithelial-mesenchymal transition; methyltransferase-like 14; non-small cell lung cancer
    DOI:  https://doi.org/10.3892/ol.2021.13108
  6. Clin Exp Pharmacol Physiol. 2021 Oct 30.
    The RNA N6 -methyladenosine modulator HNRNPA2B1 is involved in the development of non-small cell lung cancer.
    Luming Jin, Chaoyang Chen, Jianyu Yao, Zhichen Yu, Liang Bu.
      The key N6 methyladenosine (m6 A) RNA methylation regulator is associated with multiple tumor progression. However, the m6 A-associated regulators that influence non-small-cell lung cancer (NSCLC) development have not been fully clarified. The m6 A regulator expression pattern of NSCLC patients from the TCGA dataset was identified. Aberrations of m6A modulators are related to NSCLC development via cBioPortal database. Furthermore, we found that IGF2BP2, IGF2BP3, HNRNPA2B1, and FTO are significantly correlated with advanced stage disease or clinical outcomes in NSCLC by UALCAN and Kaplan-Meier plot. Bioinformatics analysis showed that m6 A modulators (IGF2BP2, IGF2BP3, HNRNPA2B1, and FTO) are associated with immunomodulator and immune infiltration expression in NSCLC via TIMER database. The co-expression between these m6A-associated modulators was analyzed by protein-protein interaction networks. Finally, we found that HNRNPA2B1 promotes NSCLC development in vitro by regulating cell proliferation and metastasis functions via CCK8 and transwell assay. Our study showed that HNRNPA2B1 is a promising target and biomarker for cancer therapy in NSCLC.
    Keywords:  HNRNPA2B1; RNA N6-methyladenosine; immune infiltration; non-small-cell lung cancer
    DOI:  https://doi.org/10.1111/1440-1681.13608
  7. Front Oncol. 2021 ;11 745719
    Identification and Validation of m6A-Related lncRNA Signature as Potential Predictive Biomarkers in Breast Cancer.
    Wenchang Lv, Yichen Wang, Chongru Zhao, Yufang Tan, Mingchen Xiong, Yi Yi, Xiao He, Yuping Ren, Yiping Wu, Qi Zhang.
      The metastasis and poor prognosis are still regarded as the main challenge in the clinical treatment of breast cancer (BC). Both N6-methyladenosine (m6A) modification and lncRNAs play vital roles in the carcinogenesis and evolvement of BC. Considering the unknown association of m6A and lncRNAs in BC, this study therefore aims to discern m6A-related lncRNAs and explore their prognostic value in BC patients. Firstly, a total of 6 m6A-related lncRNAs were screened from TCGA database and accordingly constructed a prognostic-predicting model. The BC patients were then divided into high-risk and low-risk groups dependent on the median cutoff of risk score based on this model. Then, the predictive value of this model was validated by the analyses of cox regression, Kaplan-Meier curve, ROC curve, and the biological differences in the two groups were validated by PCA, KEGG, GSEA, immune status as well as in vitro assay. Finally, we accordingly constructed a risk prognostic model based on the 6 identified m6A-related lncRNAs, including Z68871.1, AL122010.1, OTUD6B-AS1, AC090948.3, AL138724.1, EGOT. Interestingly, the BC patients were divided into the low-risk and high-risk groups with different prognoses according to the risk score. Notably, the risk score of the model was an excellent independent prognostic factor. In the clinical sample validation, m6A regulatory proteins were differentially expressed in patients with different risks, and the markers of tumor-associated macrophages and m6A regulators were co-localized in high-risk BC tissues. This well-validated risk assessment tool based on the repertoire of these m6A-related genes and m6A-related lncRNAs, is of highly prognosis-predicting ability, and might provide a supplemental screening method for precisely judging BC prognosis.
    Keywords:  breast cancer; immune infiltration; lncRNA; m6A; prognostic signature
    DOI:  https://doi.org/10.3389/fonc.2021.745719
  8. Bioengineered. 2021 Nov 05.
    N6-Methyladenosine-regulated LINC00675 Suppress the Proliferation, Migration and Invasion of Breast Cancer cells via Inhibiting miR-513b-5p.
    Shenglan Fan, Liping Wang.
      Breast cancer (BC) is the most common cancer among women. LINC00675 and miR-513b-5p has been reported to be abnormally expressed in multiple types of cancers and modulate malignant phenotypes of cancer cells. However, to date, the functional role and underlying regulatory mechanism of LINC00675 and miR-513b-5p in BC remains largely unknown. Here, we found that LINC00675 was significantly downregulated in BC tissues and cell lines. Decrease of LINC00675 expression associated with higher tumor grade, lymphovascular invasion and shorter survival in BC patients. Functional experiments demonstrated that overexpression of LINC00675 suppressed BC cell proliferation, migration and invasion, whereas depletion of LINC00675 exerted opposite effects. Mechanistically, LINC00675 functioned as a competing endogenous RNA (ceRNA) to interact with miR-513b-5p and suppress its expression. Moreover, METTL3 increased the m6A methylation of LINC00675, which enhanced the association between LINC00675 and miR-513b-5p. Collectively, the central findings of our study suggest that LINC00675 represses BC progression through the inhibition of miR-513b-5p in a m6A-dependent manner.
    Keywords:  METTL3; ceRNA; m6A methylation; miR-513b-5p
    DOI:  https://doi.org/10.1080/21655979.2021.2001905
  9. Cell Death Discov. 2021 Nov 01. 7(1): 329
    FTO promotes tumour proliferation in bladder cancer via the FTO/miR-576/CDK6 axis in an m6A-dependent manner.
    Guanwen Zhou, Keqiang Yan, Jikai Liu, Lijian Gao, Xianzhou Jiang, Yidong Fan.
      The aberrant expression of fat mass and obesity-associated protein (FTO) has been confirmed to be associated with a variety of cancers and participates in the regulation of multiple biological behaviours. FTO plays an oncogenic role in bladder cancer, but few studies have focused on how FTO promotes bladder cancer progression by regulating miRNA synthesis. Here, we confirmed that FTO expression was significantly increased in bladder cancer and was associated with a poor prognosis. FTO overexpression promoted bladder cancer cell proliferation, whereas FTO knockdown inhibited bladder cancer cell proliferation. We also demonstrated that FTO promoted bladder cancer cell proliferation via the FTO/miR-576/CDK6 pathways. Taken together, our work revealed that FTO plays a critical role in bladder cancer and could be a potential diagnostic or prognostic biomarker for this disease.
    DOI:  https://doi.org/10.1038/s41420-021-00724-5
  10. Front Immunol. 2021 ;12 740571
    N6-Methyladenosine Methylomic Landscape of Lung Tissues in Murine Acute Allergic Asthma.
    Fangzhou Teng, Weifeng Tang, Tulake Wuniqiemu, Jingjing Qin, Yaolong Zhou, Xi Huang, Shiyuan Wang, Xueyi Zhu, Zhao Tang, La Yi, Ying Wei, Jingcheng Dong.
      Allergic asthma is well known as a common respiratory disorder comprising an allergic inflammatory nature and excessive immune characteristic. N 6-methyladenosine (m6A) methylation is an RNA epigenetic modification that post-transcriptionally regulates gene expression and function by affecting the RNA fate. Currently, m6A methylation is gaining attention as a mechanism of immunoregulation. However, whether m6A methylation engages the pathological process of asthma remains uncertain. Here, we present the m6A methylomic landscape in the lung tissues of ovalbumin-induced acute asthma mice using MeRIP-seq and RNA-seq. We identified 353 hypermethylated m6A peaks within 329 messenger RNAs (mRNAs) and 150 hypomethylated m6A peaks within 143 mRNAs in the lung tissues of asthmatic mice. These differentially methylated mRNAs were found to be involved in several immune function-relevant signaling pathways. In addition, we predicted 25 RNA-binding proteins that recognize the differentially methylated peak sites by exploring public databases, and the roles of these proteins are mostly related to mRNA biogenesis and metabolism. To further investigate the expression levels of the differentially methylated genes, we performed combined analysis of the m6A methylome and transcriptome data and identified 127 hypermethylated mRNAs (107 high and 20 low expression) and 43 hypomethylated mRNAs with differential expressions (9 high and 34 low expression). Of these, there are a list of mRNAs involved in immune function and regulation. The present results highlight the essential role of m6A methylation in the pathogenesis of asthma.
    Keywords:  MeRIP-seq; N6-methyladenosine; OVA; asthma; lung tissue; m6A; mouse
    DOI:  https://doi.org/10.3389/fimmu.2021.740571
  11. J Clin Lab Anal. 2021 Nov 05. e24071
    Comprehensive analysis of N6 -methyladenosine-related long non-coding RNAs for prognosis prediction in liver hepatocellular carcinoma.
    Hong-Xu Zhu, Wen-Jie Lu, Wei-Ping Zhu, Song Yu.
       BACKGROUND: Liver hepatocellular carcinoma (LIHC) is a lethal cancer. This study aimed to identify the N6 -methyladenosine (m6 A)-targeted long non-coding RNA (lncRNA) related to LIHC prognosis and to develop an m6 A-targeted lncRNA model for prognosis prediction in LIHC.
    METHODS: The expression matrix of mRNA and lncRNA was obtained, and differentially expressed (DE) mRNAs and lncRNAs between tumor and normal samples were identified. Univariate Cox and pathway enrichment analyses were performed on the m6 A-targeted lncRNAs and the LIHC prognosis-related m6 A-targeted lncRNAs. Prognostic analysis, immune infiltration, and gene DE analyses were performed on LIHC subgroups, which were obtained from unsupervised clustering analysis. Additionally, a multi-factor Cox analysis was used to construct a prognostic risk model based on the lncRNAs from the LASSO Cox model. Univariate and multivariate Cox analyses were used to assess prognostic independence.
    RESULTS: A total of 5031 significant DEmRNAs and 292 significant DElncRNAs were screened, and 72 LIHC-specific m6 A-targeted binding lncRNAs were screened. Moreover, a total of 29 LIHC prognosis-related m6 A-targeted lncRNAs were obtained and enriched in cytoskeletal, spliceosome, and cell cycle pathways. An 11-m6 A-lncRNA prognostic model was constructed and verified; the top 10 lncRNAs included LINC00152, RP6-65G23.3, RP11-620J15.3, RP11-290F5.1, RP11-147L13.13, RP11-923I11.6, AC092171.4, KB-1460A1.5, LINC00339, and RP11-119D9.1. Additionally, the two LIHC subgroups, Cluster 1 and Cluster 2, showed significant differences in the immune microenvironment, m6 A enzyme genes, and prognosis of LIHC.
    CONCLUSION: The m6 A-lncRNA prognostic model accurately and effectively predicted the prognostic survival of LIHC. Immune cells, immune checkpoints (ICs), and m6 A enzyme genes could act as novel therapeutic targets for LIHC.
    Keywords:  N6-methyladenosine; liver hepatocellular carcinoma; long non-coding RNA; prognosis prediction
    DOI:  https://doi.org/10.1002/jcla.24071
  12. Cell Rep Methods. 2021 Sep 27. pii: 100061. [Epub ahead of print]1(5):
    Systematic detection of m6A-modified transcripts at single-molecule and single-cell resolution.
    Kyung Lock Kim, Peter van Galen, Volker Hovestadt, Gilbert J Rahme, Ekaterina N Andreishcheva, Abhijeet Shinde, Elizabeth Gaskell, Daniel R Jones, Efrat Shema, Bradley E Bernstein.
      Epigenetic modifications control the stability and translation of mRNA molecules. Here, we present a microscopy-based platform for quantifying modified RNA molecules and for relating the modification patterns to single-cell phenotypes. We directly capture mRNAs from cell lysates on oligo-dT-coated coverslips, then visually detect and sequence individual m6A-immunolabled transcripts without amplification. Integration of a nanoscale device enabled us to isolate single cells on the platform, and thereby relate single-cell m6A modification states to gene expression signatures and cell surface markers. Application of the platform to MUTZ3 leukemia cells revealed a marked reduction in cellular m6A levels as CD34+ leukemic progenitors differentiate to CD14+ myeloid cells. We then coupled single-molecule m6A detection with fluorescence in situ hybridization (FISH) to relate mRNA and m6A levels of individual genes to single-cell phenotypes. This single-cell multi-modal assay suite can empower investigations of RNA modifications in rare populations and single cells.
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100061
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