bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–06–20
fourteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. The m6A-related gene signature for predicting the prognosis of breast cancer.
  2. N6-Methyladenosine-Related RNA Signature Predicting the Prognosis of Ovarian Cancer.
  3. Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors.
  4. METTL3‑mediated m6A modification of Bcl‑2 mRNA promotes non‑small cell lung cancer progression.
  5. m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity.
  6. Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner.
  7. Acute depletion of METTL3 implicates N6-methyladenosine in alternative intron/exon inclusion in the nascent transcriptome.
  8. METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma.
  9. m6A modification of RNA and its role in cancer, with a special focus on lung cancer.
  10. m6AGE: A Predictor for N6-Methyladenosine Sites Identification Utilizing Sequence Characteristics and Graph Embedding-Based Geometrical Information.
  11. Hakai is required for stabilization of core components of the m6A mRNA methylation machinery.
  12. sm6A RNA methylation and beyond - The epigenetic machinery and potential treatment options.
  13. Identification of an m6A-Related lncRNA Signature for Predicting the Prognosis in Patients With Kidney Renal Clear Cell Carcinoma.
  14. A heat shock-responsive lncRNA Heat acts as a HSF1-directed transcriptional brake via m6A modification.
  1. PeerJ. 2021 ;9 e11561
    The m6A-related gene signature for predicting the prognosis of breast cancer.
    Shanliang Zhong, Zhenzhong Lin, Huanwen Chen, Ling Mao, Jifeng Feng, Siying Zhou.
      N6-methyladenosine (m6A) modification has been shown to participate in tumorigenesis and metastasis of human cancers. The present study aimed to investigate the roles of m6A RNA methylation regulators in breast cancer. We used LASSO regression to identify m6A-related gene signature predicting breast cancer survival with the datasets downloaded from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA). RNA-Seq data of 3409 breast cancer patients from GSE96058 and 1097 from TCGA were used in present study. A 10 m6A-related gene signature associated with prognosis was identified from 22 m6A RNA methylation regulators. The signature divided patients into low- and high-risk group. High-risk patients had a worse prognosis than the low-risk group. Further analyses indicated that IGF2BP1 may be a key m6A RNA methylation regulator in breast cancer. Survival analysis showed that IGF2BP1 is an independent prognostic factor of breast cancer, and higher expression level of IGF2BP1 is associated with shorter overall survival of breast cancer patients. In conclusion, we identified a 10 m6A-related gene signature associated with overall survival of breast cancer. IGF2BP1 may be a key m6A RNA methylation regulator in breast cancer.
    Keywords:  Breast cancer; Breast neoplasms; IGF2BP1; Prognosis; m6A modification
    DOI:  https://doi.org/10.7717/peerj.11561
  2. Recent Pat Anticancer Drug Discov. 2021 Jun 15.
    N6-Methyladenosine-Related RNA Signature Predicting the Prognosis of Ovarian Cancer.
    Jiao Jiao, Longyang Jiang, Yang Luo.
       BACKGROUND: N6-Methyladenosine (m6A) RNA methylation is the most universal mRNA modification in eukaryotic cells. M6A mRNA modification affects almost every phases of RNA processing, including splicing, decay, export, translation and expression. Several patents have reported the application of m6A mRNA modification in cancer diagnosis and treatment. Ovarian cancer is the leading cause of death among all gynecological cancers. It is urgent to identify new biomarkers for early diagnosis and prognosis of ovarian cancer.
    OBJECTIVE: In the current study, we aimed to evaluate the m6A RNA methylation regulators and m6A related genes and establish a new gene signature panel for prognosis of ovarian cancer.
    METHOD: We downloaded the Mutations data, FPKM data and corresponding clinical information of 373 patients with ovarian cancer (OC) from the TCGA database. We performed LASSO regression analysis and multivariate cox regression analysis to develop a risk-identifying gene signature panel.
    RESULTS: A total of 317 candidate m6A RNA methylation related genes were obtained. Finally, 12 -genes (WTAP, LGR6, ZC2HC1A, SLC4A8, AP2A1, NRAS, CUX1, HDAC1, CD79A, ACE2, FLG2 and LRFN1) were selected to establish the signature panel. We analyzed the genetic alterations of the selected 12 -genes in OC using cBioPortal database. Among the 373 patients, 368 patients have mutations. The results showed that all queried genes were altered in 137 of 368 cases (37.23%). The 12-gene signature panel was confirmed as an independent prognostic indicator (P =2.29E-18, HR = 1.699, 95% CI = 1.508-1.913).
    CONCLUSION: We established an effective m6A-related gene signature panel consisted of 12 -genes, which can predict the outcome of patients with OC. The high risk score indicates unfavorable survival. Our study provided novel insights into the relationship between m6A and OC. This gene signature panel will be helpful in identifying poor prognostic patients with OC and could be a promising prognostic indicator in clinical practice.
    Keywords:  N6-Methyladenosine; methylation; ovarian cancer; prognostic indicator; biomarkers; tumorigenesis
    DOI:  https://doi.org/10.2174/1574892816666210615164645
  3. Front Cell Dev Biol. 2021 ;9 676364
    Role of RNA N6-Methyladenosine Modification in Male Infertility and Genital System Tumors.
    Shuai Liu, Yongfeng Lao, Yanan Wang, Rongxin Li, Xuefeng Fang, Yunchang Wang, Xiaolong Gao, Zhilong Dong.
      Epigenetic alterations, particularly RNA methylation, play a crucial role in many types of disease development and progression. Among them, N6-methyladenosine (m6A) is the most common epigenetic RNA modification, and its important roles are not only related to the occurrence, progression, and aggressiveness of tumors but also affect the progression of many non-tumor diseases. The biological effects of RNA m6A modification are dynamically and reversibly regulated by methyltransferases (writers), demethylases (erasers), and m6A binding proteins (readers). This review summarized the current finding of the RNA m6A modification regulators in male infertility and genital system tumors and discussed the role and potential clinical application of the RNA m6A modification in spermatogenesis and male genital system tumors.
    Keywords:  N6-methyladenosine; RNA methylation; genital system tumors; male fertility; spermatogenesis
    DOI:  https://doi.org/10.3389/fcell.2021.676364
  4. Oncol Rep. 2021 Aug;pii: 163. [Epub ahead of print]46(2):
    METTL3‑mediated m6A modification of Bcl‑2 mRNA promotes non‑small cell lung cancer progression.
    Yongxi Zhang, Shuyuan Liu, Tiesuo Zhao, Chengxue Dang.
      Methyltransferase‑like 3 (METTL3) is an RNA methyltransferase that mediates modification of N6‑methyladenosine (m6A), which serves as an oncogene in various types of cancer. The role of m6A modification in the onset and progression of cancer has attracted growing attention. However, the functional and regulatory mechanisms of METTL3 in non‑small cell lung cancer (NSCLC) progression are still poorly understood. In the present study, METTL3 expression in NSCLC tissue was analyzed using the Gene Expression Profiling Interactive Analysis database. Western blotting and reverse transcription‑quantitative PCR were performed to evaluate the expression of METTL3 in NSCLC tissue and cell lines. Here, knockdown and overexpression of METTL3 notably decreased NSCLC cell viability, apoptosis and migration in vitro and, as well as tumorigenicity in vivo. Expression of METTL3 was upregulated in NSCLC tissue. METTL3 overexpression promoted cell viability and migration in NSCLC, while knockdown of METTL3 yielded the opposite result in vivo and in vitro. METTL3 increased Bcl‑2 translation via m6A modification, which increased viability and enhanced migration of NSCLC cells. METTL3 served as an oncogene in NSCLC via METTL3‑mediated Bcl‑2 mRNA m6A modification, which indicated that targeting METTL3 may be an effective therapeutic strategy for clinical management of NSCLC.
    Keywords:  Bcl‑2; N6‑methyladenosine; methyltransferase‑like 3; non‑small cell lung cancer
    DOI:  https://doi.org/10.3892/or.2021.8114
  5. Sci Adv. 2021 Jun;pii: eabg0470. [Epub ahead of print]7(25):
    m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity.
    Jing Zhou, Xingli Zhang, Jiajia Hu, Rihao Qu, Zhibin Yu, Hao Xu, Huifang Chen, Lichong Yan, Chenbo Ding, Qiang Zou, Youqiong Ye, Zhengting Wang, Richard A Flavell, Hua-Bing Li.
      N6-methyladenosine (m6A) modification is dynamically regulated by "writer" and "eraser" enzymes. m6A "writers" have been shown to ensure the homeostasis of CD4+ T cells, but the "erasers" functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell-specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.
    DOI:  https://doi.org/10.1126/sciadv.abg0470
  6. Pain. 2021 Jul 01. 162(7): 1960-1976
    Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner.
    Zhiqiang Pan, Qi Zhang, Xiaodan Liu, Huimin Zhou, Tong Jin, Ling-Yun Hao, Ling Xie, Ming Zhang, Xiao-Xiao Yang, Meng-Lan Sun, Zhou-Ya Xue, Yang Tao, Xin-Chun Ye, Wen Shen, Jun-Li Cao.
       ABSTRACT: The methyltransferase-like 3 (Mettl3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for RNA N6-methyladenosine (m6A) modification, which plays an important role in gene post-transcription modulation. Although RNA m6A is enriched in mammalian neurons, its regulatory function in nociceptive information processing remains elusive. Here, we reported that Complete Freund's Adjuvant (CFA)-induced inflammatory pain significantly decreased global m6A level and m6A writer Mettl3 in the spinal cord. Mimicking this decease by knocking down or conditionally deleting spinal Mettl3 elevated the levels of m6A in ten-eleven translocation methylcytosine dioxygenases 1 (Tet1) mRNA and TET1 protein in the spinal cord, leading to production of pain hypersensitivity. By contrast, overexpressing Mettl3 reversed a loss of m6A in Tet1 mRNA and blocked the CFA-induced increase of TET1 in the spinal cord, resulting in the attenuation of pain behavior. Furthermore, the decreased level of spinal YT521-B homology domain family protein 2 (YTHDF2), an RNA m6A reader, stabilized upregulation of spinal TET1 because of the reduction of Tet1 mRNA decay by the binding to m6A in Tet1 mRNA in the spinal cord after CFA. This study reveals a novel mechanism for downregulated spinal cord METTL3 coordinating with YTHDF2 contributes to the modulation of inflammatory pain through stabilizing upregulation of TET1 in spinal neurons.
    DOI:  https://doi.org/10.1097/j.pain.0000000000002218
  7. Genome Res. 2021 Jun 15. pii: gr.271635.120. [Epub ahead of print]
    Acute depletion of METTL3 implicates N6-methyladenosine in alternative intron/exon inclusion in the nascent transcriptome.
    Guifeng Wei, Mafalda Almeida, Greta Pintacuda, Heather Coker, Joseph S Bowness, Jernej Ule, Neil Brockdorff.
      RNA N6-methyladenosine (m6A) modification plays important roles in multiple aspects of RNA regulation. m6A is installed cotranscriptionally by the METTL3/14 complex, but its direct roles in RNA processing remain unclear. Here we investigate the presence of m6A in nascent RNA of mouse embryonic stem cells. We find that around 10% of m6A peaks are located in alternative introns/exons, often close to 5' splice sites. m6A peaks significantly overlap with RBM15 RNA-binding sites and the histone modification H3K36me3. Acute depletion of METTL3 disrupts inclusion of alternative introns/exons in the nascent transcriptome, particularly at 5' splice sites that are proximal to m6A peaks. For terminal or variable-length exons, m6A peaks are generally located on or immediately downstream of a 5' splice site that is suppressed in the presence of m6A, and upstream of a 5' splice site that is promoted in the presence of m6A. Genes with the most immediate effects on splicing include several components of the m6A pathway, suggesting an autoregulatory function. Collectively, our findings demonstrate crosstalk between the m6A machinery and the regulation of RNA splicing.
    DOI:  https://doi.org/10.1101/gr.271635.120
  8. Front Genet. 2021 ;12 609174
    METTL14 Acts as a Potential Regulator of Tumor Immune and Progression in Clear Cell Renal Cell Carcinoma.
    Tianbo Xu, Su Gao, Hailong Ruan, Jingchong Liu, Yuenan Liu, Di Liu, Junwei Tong, Jian Shi, Hongmei Yang, Ke Chen, Xiaoping Zhang.
      Clear cell renal cell carcinoma (ccRCC) is characterized by its insensitivity to chemoradiotherapy and lacks effective diagnostic and prognostic biomarkers. In this study, we focused on the role of m6A RNA methylation regulators for tumor immunity. Based on the expression of 20 m6A regulators, consensus clustering was performed to divide patients into cluster1/cluster2 and showed that there was a survival difference between the two clusters. Through cox regression analysis, five hub m6A regulators were screened to construct a risk model. Further analysis showed that the risk score was an independent prognostic factor. GSEA, GSVA, and KEGG analysis revealed that immune cell pathways played a critical role between the high risk group and low risk group. Combined with CIBERSORT and survival analysis, five hub tumor-infiltrating immune cells (TIICs) were identified for further study. Meanwhile, correlation analysis indicated that IGF2BP2 was positively associated with activated memory CD4 T cell and METTL14 was negatively correlated to the regulatory T cell. Therefore, IGF2BP2 and METTL14 were regarded as key genes. Further study verified that only METTL14 possessed good diagnostic and prognostic value. Then, GSEA exhibited that METTL14 was mainly enriched in chemokine related pathways. We also found that CCL5 was negatively correlated to METTL14 and might serve as a potential target of METTL14. In conclusion, these findings suggest that the METTL14/CCL5/Tregs axis is a potential signaling pathway for regulating tumor immunity, and might become novel therapeutic targets for ccRCC.
    Keywords:  CCL5; METTL14; clear cell renal cell carcinoma; m6A RNA methylation; regulatory T cell; tumor immunity; tumor progression
    DOI:  https://doi.org/10.3389/fgene.2021.609174
  9. Genomics. 2021 Jun 09. pii: S0888-7543(21)00230-5. [Epub ahead of print]
    m6A modification of RNA and its role in cancer, with a special focus on lung cancer.
    Raja Ishaq Nabi Khan, Waseem Akram Malla.
      Epitranscriptomics involves functionally relevant biochemical modifications of RNA taking place at the transcriptome level without a change in the sequence of ribonucleotides. Several types of modifications that affect the processing and function of differentRNA types have been reported. Methylation at N6 of Adenosine called m6A is one such modification, quite widespread in occurrence and reported in snRNAs, lncRNAs, circRNAs, rRNAs, miRNAs, and most abundantly, in mRNAs. The significant implications of m6A in various types of cancers are being widely recognized. Here, we give a brief about the enzymes that install the m6A modification (= m6A writers), that remove it (= m6A erasers) and certain RNA binding proteins (= m6A readers) which affect the fate of the m6A-containing RNA by recruiting various proteins. We also discuss the relevance of m6A in ncRNAs in various cancer types, followed by a discussion on the role of m6A of RNA in lung cancer.
    Keywords:  Cancer; Circular RNA; lncRNAs; m6A; miRNAs
    DOI:  https://doi.org/10.1016/j.ygeno.2021.06.013
  10. Front Genet. 2021 ;12 670852
    m6AGE: A Predictor for N6-Methyladenosine Sites Identification Utilizing Sequence Characteristics and Graph Embedding-Based Geometrical Information.
    Yan Wang, Rui Guo, Lan Huang, Sen Yang, Xuemei Hu, Kai He.
      N6-methyladenosine (m6A) is one of the most prevalent RNA post-transcriptional modifications and is involved in various vital biological processes such as mRNA splicing, exporting, stability, and so on. Identifying m6A sites contributes to understanding the functional mechanism and biological significance of m6A. The existing biological experimental methods for identifying m6A sites are time-consuming and costly. Thus, developing a high confidence computational method is significant to explore m6A intrinsic characters. In this study, we propose a predictor called m6AGE which utilizes sequence-derived and graph embedding features. To the best of our knowledge, our predictor is the first to combine sequence-derived features and graph embeddings for m6A site prediction. Comparison results show that our proposed predictor achieved the best performance compared with other predictors on four public datasets across three species. On the A101 dataset, our predictor outperformed 1.34% (accuracy), 0.0227 (Matthew's correlation coefficient), 5.63% (specificity), and 0.0081 (AUC) than comparing predictors, which indicates that m6AGE is a useful tool for m6A site prediction. The source code of m6AGE is available at https://github.com/bokunoBike/m6AGE.
    Keywords:  CatBoost; feature fusion; graph embedding; m6A; machine learning
    DOI:  https://doi.org/10.3389/fgene.2021.670852
  11. Nat Commun. 2021 Jun 18. 12(1): 3778
    Hakai is required for stabilization of core components of the m6A mRNA methylation machinery.
    Praveen Bawankar, Tina Lence, Chiara Paolantoni, Irmgard U Haussmann, Migle Kazlauskiene, Dominik Jacob, Jan B Heidelberger, Florian M Richter, Mohanakarthik P Nallasivan, Violeta Morin, Nastasja Kreim, Petra Beli, Mark Helm, Martin Jinek, Matthias Soller, Jean-Yves Roignant.
      N6-methyladenosine (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila and human cells. In Drosophila, its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerization and interaction with other members of the m6A machinery, while its catalytic activity is dispensable. Finally, we demonstrate that the loss of Hakai destabilizes several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Our work adds functional and molecular insights into the mechanism of the m6A mRNA writer complex.
    DOI:  https://doi.org/10.1038/s41467-021-23892-5
  12. Drug Discov Today. 2021 Jun 12. pii: S1359-6446(21)00276-2. [Epub ahead of print]
    sm6A RNA methylation and beyond - The epigenetic machinery and potential treatment options.
    Sabrina Garbo, Clemens Zwergel, Cecilia Battistelli.
      m6A is emerging as one of the most important RNA modifications because of its involvement in pathological and physiological events. Here, we provide an overview of this epitranscriptomic modification, beginning with a description of the molecular players involved and continuing with a focus on the role of m6A in the maintenance of stemness, induction of the epithelial to mesenchymal transition (EMT), and tumor progression. Finally, we discuss the state of the art regarding the design and validation of inhibitors of m6A writers or erasers to provide a background for future investigations and for the development of specific therapeutics.
    Keywords:  Cancer; Epitranscriptomics; METTL3; RNA; m6A
    DOI:  https://doi.org/10.1016/j.drudis.2021.06.004
  13. Front Oncol. 2021 ;11 663263
    Identification of an m6A-Related lncRNA Signature for Predicting the Prognosis in Patients With Kidney Renal Clear Cell Carcinoma.
    JunJie Yu, WeiPu Mao, Si Sun, Qiang Hu, Can Wang, ZhiPeng Xu, RuiJi Liu, SaiSai Chen, Bin Xu, Ming Chen.
       Purpose: This study aimed to construct an m6A-related long non-coding RNAs (lncRNAs) signature to accurately predict the prognosis of kidney clear cell carcinoma (KIRC) patients using data obtained from The Cancer Genome Atlas (TCGA) database.
    Methods: The KIRC patient data were downloaded from TCGA database and m6A-related genes were obtained from published articles. Pearson correlation analysis was implemented to identify m6A-related lncRNAs. Univariate, Lasso, and multivariate Cox regression analyses were used to identifying prognostic risk-associated lncRNAs. Five lncRNAs were identified and used to construct a prognostic signature in training set. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were applied to evaluate reliability and sensitivity of the signature in testing set and overall set, respectively. A prognostic nomogram was established to predict the probable 1-, 3-, and 5-year overall survival of KIRC patients quantitatively. GSEA was performed to explore the potential biological processes and cellular pathways. Besides, the lncRNA/miRNA/mRNA ceRNA network and PPI network were constructed based on weighted gene co-expression network analysis (WGCNA). Functional Enrichment Analysis was used to identify the biological functions of m6A-related lncRNAs.
    Results: We constructed and verified an m6A-related lncRNAs prognostic signature of KIRC patients in TCGA database. We confirmed that the survival rates of KIRC patients with high-risk subgroup were significantly poorer than those with low-risk subgroup in the training set and testing set. ROC curves indicated that the prognostic signature had a reliable predictive capability in the training set (AUC = 0.802) and testing set (AUC = 0.725), respectively. Also, we established a prognostic nomogram with a high C-index and accomplished good prediction accuracy. The lncRNA/miRNA/mRNA ceRNA network and PPI network, as well as functional enrichment analysis provided us with new ways to search for potential biological functions.
    Conclusions: We constructed an m6A-related lncRNAs prognostic signature which could accurately predict the prognosis of KIRC patients.
    Keywords:  M6A; The Cancer Genome Atlas; kidney renal clear cell carcinoma; long non-coding RNA; prognostic signature
    DOI:  https://doi.org/10.3389/fonc.2021.663263
  14. Proc Natl Acad Sci U S A. 2021 Jun 22. pii: e2102175118. [Epub ahead of print]118(25):
    A heat shock-responsive lncRNA Heat acts as a HSF1-directed transcriptional brake via m6A modification.
    Quanquan Ji, Xin Zong, Yuanhui Mao, Shu-Bing Qian.
      Long noncoding RNAs (lncRNAs) are key regulators of gene expression in diverse cellular contexts and biological processes. Given the surprising range of shapes and sizes, how distinct lncRNAs achieve functional specificity remains incompletely understood. Here, we identified a heat shock-inducible lncRNA, Heat, in mouse cells that acts as a transcriptional brake to restrain stress gene expression. Functional characterization reveals that Heat directly binds to heat shock transcription factor 1 (HSF1), thereby targeting stress genes in a trans-acting manner. Intriguingly, Heat is heavily methylated in the form of m6A. Although dispensable for HSF1 binding, Heat methylation is required for silencing stress genes to attenuate heat shock response. Consistently, m6A depletion results in prolonged activation of stress genes. Furthermore, Heat mediates these effects via the nuclear m6A reader YTHDC1, forming a transcriptional silencing complex for stress genes. Our study reveals a crucial role of nuclear epitranscriptome in the transcriptional regulation of heat shock response.
    Keywords:  RNA modification; heat shock stress; long noncoding RNA
    DOI:  https://doi.org/10.1073/pnas.2102175118
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