bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–04–11
twelve papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. RNA Modification of N6-Methyladenosine Predicts Immune Phenotypes and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma.
  2. Comprehensive Analysis of Differential m6A RNA Methylomes in the Hippocampus of Cocaine-Conditioned Mice.
  3. The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer.
  4. WHISTLE: A Functionally Annotated High-Accuracy Map of Human m6A Epitranscriptome.
  5. Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma.
  6. MeT-DB V2.0: Elucidating Context-Specific Functions of N6-Methyl-Adenosine Methyltranscriptome.
  7. YTHDF1 Aggravates the Progression of Cervical Cancer Through m6A-Mediated Up-Regulation of RANBP2.
  8. KDM5B promotes self-renewal of hepatocellular carcinoma cells through the microRNA-448-mediated YTHDF3/ITGA6 axis.
  9. WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA.
  10. The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis.
  11. MODOMICS: An Operational Guide to the Use of the RNA Modification Pathways Database.
  12. Integrated Analysis of mRNA-m6A-protein Profiles Reveals Novel Insights into the Mechanisms for Cadmium-induced Urothelial Transformation.
  1. Front Oncol. 2021 ;11 642159
    RNA Modification of N6-Methyladenosine Predicts Immune Phenotypes and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma.
    Huihuang Li, Jiao Hu, Anze Yu, Belaydi Othmane, Tao Guo, Jinhui Liu, Chunliang Cheng, Jinbo Chen, Xiongbing Zu.
      RNA modification of N6-methyladenosine (m6A) plays critical roles in various biological processes, such as cancer development, inflammation, and the anticancer immune response. However, the role played by a comprehensive m6A modification pattern in regulating anticancer immunity in kidney renal clear cell carcinoma (KIRC) has not been fully elucidated. In this study, we identified two independent m6A modification patterns with distinct biological functions, immunological characteristics, and prognoses in KIRC. Next, we developed an m6A score algorithm to quantify an individual's m6A modification pattern, which was independently validated in external cohorts. The m6A cluster 1 and low m6A score groups were characterized by a hot tumor microenvironment with an increased infiltration level of cytotoxic immune cells, higher tumor mutation burden, higher immune checkpoint expression, and decreased stroma-associated signature enrichment. In general, the m6A cluster 1 and low m6A score groups reflected an inflammatory phenotype, which may be more sensitive to anticancer immunotherapy. The m6A cluster 2 and high m6A score groups indicated a non-inflammatory phenotype, which may not be sensitive to immunotherapy but rather to targeted therapy. In this study, we first identified m6A clusters and m6A scores to elucidate immune phenotypes and to predict the prognosis and immunotherapy response in KIRC, which can guide urologists for making more precise clinical decisions.
    Keywords:  N6-methyladenosine; immune checkpoint blockade; immune phenotype; kidney renal clear cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.642159
  2. Mol Neurobiol. 2021 Apr 07.
    Comprehensive Analysis of Differential m6A RNA Methylomes in the Hippocampus of Cocaine-Conditioned Mice.
    Aiqin Xue, Yan Huang, Meng Li, Qian Wei, Qian Bu.
      N6-methyladenosine (m6A) is the most prevalent internal modification found in mRNAs and lncRNA and plays a vital role in posttranscriptional regulation in mammals. m6A is abundant in the nervous system, where it modulates neuronal development and hippocampus-dependent learning and memory. However, the roles of RNAs m6A modification and its related enzymes in cocaine reward are still not fully understood. In this study, we found that the fat mass and obesity-associated gene (FTO) demethylase, but not methyltransferase-like 3 (METTL3) and 14 (METTL14), was downregulated in the hippocampus following cocaine-induced conditioned place preference (CPP), and the level of m6A is notably higher in the hippocampus of cocaine CPP training mice. Using methylated m6A RNA immunoprecipitation sequencing (MeRIP-m6A-seq), we identified a total of 6516 m6A peaks within 4460 mRNAs, and 3083 m6A peaks within 850 lncRNAs were significantly dysregulated. Intriguingly, the altered m6A peaks within mRNAs and lncRNAs were enriched in synapse maturation and localization processes. Our study uncovers a critical role for an m6A epitranscriptomic dysregulation and downregulation of FTO expression in the hippocampus following cocaine-induced CPP.
    Keywords:  Cocaine; Synapse; Hippocampus; MeRIP-m6A-seq
    DOI:  https://doi.org/10.1007/s12035-021-02363-4
  3. Cell Biosci. 2021 Apr 09. 11(1): 72
    The crucial roles of N6-methyladenosine (m6A) modification in the carcinogenesis and progression of colorectal cancer.
    Zhihao Fang, Yiqiu Hu, Jinhui Hu, Yanqin Huang, Shu Zheng, Cheng Guo.
      As the predominant modification in RNA, N6-methyladenosine (m6A) has attracted increasing attention in the past few years since it plays vital roles in many biological processes. This chemical modification is dynamic, reversible and regulated by several methyltransferases, demethylases and proteins that recognize m6A modification. M6A modification exists in messenger RNA and affects their splicing, nuclear export, stability, decay, and translation, thereby modulating gene expression. Besides, the existence of m6A in noncoding RNAs (ncRNAs) could also directly or indirectly regulated gene expression. Colorectal cancer (CRC) is a common cancer around the world and of high mortality. Increasing evidence have shown that the changes of m6A level and the dysregulation of m6A regulatory proteins have been implicated in CRC carcinogenesis and progression. However, the underlying regulation laws of m6A modification to CRC remain elusive and better understanding of these mechanisms will benefit the diagnosis and therapy. In the present review, the latest studies about the dysregulation of m6A and its regulators in CRC have been summarized. We will focus on the crucial roles of m6A modification in the carcinogenesis and development of CRC. Moreover, we will also discuss the potential applications of m6A modification in CRC diagnosis and therapeutics.
    Keywords:  Coding and noncoding RNA; Colorectal cancer; N6-methyladenosine; RNA methylation
    DOI:  https://doi.org/10.1186/s13578-021-00583-8
  4. Methods Mol Biol. 2021 ;2284 519-529
    WHISTLE: A Functionally Annotated High-Accuracy Map of Human m6A Epitranscriptome.
    Qingru Xu, Kunqi Chen, Jia Meng.
      N6-Methyladenosine (m6A) is the most prevalent posttranscriptional modification in eukaryotes and plays a pivotal role in various biological processes, such as splicing, RNA degradation, and RNA-protein interaction. Accurately identification of the location of m6A is essential for related downstream studies. In this chapter, we introduce a prediction framework WHISTLE, which enables us to acquire so far the most accurate map of the transcriptome-wide human m6A RNA-methylation sites (with an average AUC: 0.948 and 0.880 under the full transcript or mature messenger RNA models, respectively, when tested on independent datasets). Besides, each individual m6A site was also functionally annotated according to the "guilt-by-association" principle by integrating RNA methylation data, gene expression data and protein-protein interaction data. A web server was constructed for conveniently querying the predicted RNA methylation sites and their putative biological functions. The website supports the query by genes, by GO function, table view, and the download of all the functionally annotated map of predicted map of human m6A epitranscriptome. The WHISTLE web server is freely available at: www.xjtlu.edu.cn/biologicalsciences/whistle and http://whistle-epitranscriptome.com .
    Keywords:  Epitranscriptome; Guilt-by-association; Machine learning; N6-Methyladenosine (m6A); RNA modifications
    DOI:  https://doi.org/10.1007/978-1-0716-1307-8_28
  5. Front Oncol. 2021 ;11 629718
    Molecular Characteristics, Prognostic Value, and Immune Characteristics of m6A Regulators Identified in Head and Neck Squamous Cell Carcinoma.
    Xiuchao Geng, Yuhao Zhang, Zhaomu Zeng, Zhongrui Zhu, Hong Wang, Wentao Yu, Qiang Li.
      N6-methyladenosine (m6A) plays crucial roles in a diverse range of physiological and pathological processes, and it is believed that it tremendously promotes neoplasia and progression. However, knowledge of the molecular characteristics of m6A modification, its prognostic value, and the infiltration of immune cell populations in head and neck squamous cell carcinoma (HNSCC) is still insufficient. Therefore, a pan-cancer genomic analysis was systematically performed here by examining m6A regulators at the molecular level within 33 multiple cancer types, and the correlations between the expression of m6A molecules were researched using datasets from The Cancer Genome Atlas (TCGA). Based on the above analysis, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is upregulated in HNSCC and may serve as an independent prognostic factor of overall survival, thus showing potential as a prognostic biomarker in HNSCC. Genetic alteration analyses elucidated the reasons for the abnormal upregulation of IGF2BP2 in HNSCC. As a result, IGF2BP2 was selected for further univariate and multivariate analyses. The functions of the related genes were annotated through gene set enrichment analysis, and the activation states of multiple biological pathways were shown by gene set variation analysis. We found that LRRC59 and STIP1 may act as IGF2BP2-associated genes to have a regulatory function in the m6A modification. In addition, we found that the status of immune cell infiltration was correlated with the level of IGF2BP2 gene expression. Our results provide supplementation at the molecular level for epigenetic regulation in HNSCC and insight into effective immunotherapy targets and strategies.
    Keywords:  IGF2BP2; head and neck squamous cell carcinoma (HNSCC); immune cell infiltration; m6A regulators; pan-cancer; prognosis
    DOI:  https://doi.org/10.3389/fonc.2021.629718
  6. Methods Mol Biol. 2021 ;2284 507-518
    MeT-DB V2.0: Elucidating Context-Specific Functions of N6-Methyl-Adenosine Methyltranscriptome.
    Hui Liu, Jiani Ma, Jia Meng, Lin Zhang.
      N6-methyladenosine (m6A) is the most prevalent posttranscriptional modification in eukaryotes and plays a pivotal role in various biological processes. A knowledge base with the systematic collection and curation of context specific transcriptome-wide methylations is critical for elucidating their biological functions as well as for developing bioinformatics tools. In this chapter, we present a comprehensive platform MeT-DB V2.0 for elucidating context-specific functions of N6-methyl-adenosine methyltranscriptome. Met-DB V2.0 database contains context specific m6A peaks and single-base sites predicted from 185 samples for 7 species from 26 independent studies. Moreover, it is also integrated with a new database for targets of m6A readers, erasers and writers and expanded with more collections of functional data. The Met-DB V2.0 web interface and genome browser provide more friendly, powerful, and informative ways to query and visualize the data. More importantly, MeT-DB V2.0 offers for the first time a series of tools specifically designed for understanding m6A functions. The MeT-DB V2.0 web server is freely available at: http://compgenomics.utsa.edu/MeTDB and www.xjtlu.edu.cn/metdb2 .
    Keywords:  Epitranscriptome; MicroRNA; N6-methyladenosine (m6A); RNA modifications; Single-nucleotide polymorphisms (SNPs); Splicing factors
    DOI:  https://doi.org/10.1007/978-1-0716-1307-8_27
  7. Front Oncol. 2021 ;11 650383
    YTHDF1 Aggravates the Progression of Cervical Cancer Through m6A-Mediated Up-Regulation of RANBP2.
    Haocheng Wang, Qingya Luo, Jianyi Kang, Qinglv Wei, Yu Yang, Dan Yang, Xiaoyi Liu, Tao Liu, Ping Yi.
      N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various cancers. YTHDF1 acts as a crucial m6A "reader" and regulates the fate of m6A modified mRNA. However, its role in cervical cancer remains unknown. In this study, we showed that YTHDF1 was highly expressed in cervical cancer, and was closely associated with the poor prognosis of cervical cancer patients. YTHDF1 knockdown suppressed the growth, migration and invasion, and induced apoptosis of cervical cancer cells. Moreover, YTHDF1 knockdown inhibited tumorigenesis of cervical cancer cells in vivo. Through combined on-line data analysis of RIP-seq, meRIP-seq and Ribo-seq upon YTHDF1 knockdown, RANBP2 was identified as the key target of YTHDF1 in cervical cancer cells. YTHDF1 regulated RANBP2 translation in an m6A-dependent manner without effect on its mRNA expression. RANBP2 potentiated the growth, migration and invasion of cervical cancer cells. Our study demonstrated the oncogenic role of YTHDF1 in cervical cancer by regulating RANBP2 expression and YTHDF1 represents a potential target for cervical cancer therapy.
    Keywords:  N6-methyladenosine; RANBP2; YTHDF1; cervical cancer; tumorigenicity
    DOI:  https://doi.org/10.3389/fonc.2021.650383
  8. J Cell Mol Med. 2021 Apr 07.
    KDM5B promotes self-renewal of hepatocellular carcinoma cells through the microRNA-448-mediated YTHDF3/ITGA6 axis.
    Jun-Cheng Guo, Zhuo Liu, Yi-Jun Yang, Min Guo, Jian-Quan Zhang, Jin-Fang Zheng.
      Histone methylation plays important roles in mediating the onset and progression of various cancers, and lysine-specific demethylase 5B (KDM5B), as a histone demethylase, is reported to be an oncogene in hepatocellular carcinoma (HCC). However, the mechanism underlying its tumorigenesis remains undefined. Hence, we explored the regulatory role of KDM5B in HCC cells, aiming to identify novel therapeutic targets for HCC. Gene Expression Omnibus database and StarBase were used to predict important regulatory pathways related to HCC. Then, the expression of KDM5B and microRNA-448 (miR-448) in HCC tissues was detected by RT-qPCR and Western blot analysis. The correlation between KDM5B and miR-448 expression was analysed by Pearson's correlation coefficient and ChIP experiments, and the targeting of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) by miR-448 was examined by luciferase assay. Additionally, the effect of KDM5B on the proliferation, migration, invasion and apoptosis as well as tumorigenicity of transfected cells was assessed using ectopic expression and depletion experiments. KDM5B was highly expressed in HCC cells and was inversely related to miR-448 expression. KDM5B demethylated H3K4me3 on the miR-448 promoter and thereby inhibited the expression of miR-448, which in turn targeted YTHDF3 and integrin subunit alpha 6 (ITGA6) to promote the malignant phenotype of HCC. Moreover, KDM5B accelerated HCC progression in nude mice via the miR-448/YTHDF3/ITGA6 axis. Our study uncovered that KDM5B regulates the YTHDF3/ITGA6 axis by inhibiting the expression of miR-448 to promote the occurrence of HCC.
    Keywords:  YTH N6-methyladenosine RNA binding protein 3; demethylation; hepatocellular carcinoma; integrin subunit alpha 6; lysine-specific demethylase 5B; m6A modification; microRNA-448; self-renewal
    DOI:  https://doi.org/10.1111/jcmm.16342
  9. Aging (Albany NY). 2021 Mar 26. 13
    WTAP promotes myocardial ischemia/reperfusion injury by increasing endoplasmic reticulum stress via regulating m6A modification of ATF4 mRNA.
    Jiayi Wang, Jiehan Zhang, Yan Ma, Yuxiao Zeng, Cheng Lu, Fenghua Yang, Nianxin Jiang, Xuan Zhang, Yuhua Wang, Yinghui Xu, Hanjing Hou, Shengyang Jiang, Shaowei Zhuang.
      Myocardial infarction (MI) is one of the leading causes of death. Wilms' tumor 1-associating protein (WTAP), one of the components of the m6A methyltransferase complex, has been shown to affect gene expression via regulating mRNA modification. Although WTAP has been implicated in various diseases, its role in MI is unclear. In this study, we found that hypoxia/reoxygenation (H/R) time-dependently increased WTAP expression, which in turn promoted endoplasmic reticulum (ER) stress and apoptosis, in human cardiomyocytes (AC16). H/R effects on ER stress and apoptosis were all blocked by silencing of WTAP, promoted by WTAP overexpression, and ameliorated by administration of ER stress inhibitor, 4-PBA. We then investigated the underlying molecular mechanism and found that WTAP affected m6A methylation of ATF4 mRNA to regulate its expression, and that the inhibitory effects of WTAP on ER stress and apoptosis were ATF4 dependent. Finally, WTAP's effects on myocardial I/R injury were confirmed in vivo. WTAP promoted myocardial I/R injury through promoting ER stress and cell apoptosis by regulating m6A modification of ATF4 mRNA. These findings highlight the importance of WTAP in I/R injury and provide new insights into therapeutic strategies for MI.
    Keywords:  I/R injury; Wilms' tumor 1-associating protein; endoplasmic reticulum stress; m6A modification; myocardial infarction
    DOI:  https://doi.org/10.18632/aging.202770
  10. Mol Cancer. 2021 Apr 04. 20(1): 61
    The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis.
    Mohammad Burhan Uddin, Zhishan Wang, Chengfeng Yang.
      The m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.
    Keywords:  Carcinogenesis; Cell transformation; Epitranscriptomics; Signal transduction; m6A
    DOI:  https://doi.org/10.1186/s12943-021-01356-0
  11. Methods Mol Biol. 2021 ;2284 481-505
    MODOMICS: An Operational Guide to the Use of the RNA Modification Pathways Database.
    Pietro Boccaletto, Błażej Bagiński.
      MODOMICS is an established database of RNA modifications that provides comprehensive information concerning chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. This chapter covers the resources available on MODOMICS web server and the basic steps that can be undertaken by the user to explore them. MODOMICS is available at http://www.genesilico.pl/modomics .
    Keywords:  Database; Enzymes; Epitranscriptomics; Metabolic pathways; RNA; Ribonucleoside modification; Systems biology
    DOI:  https://doi.org/10.1007/978-1-0716-1307-8_26
  12. Biomarkers. 2021 Apr 08. 1-23
    Integrated Analysis of mRNA-m6A-protein Profiles Reveals Novel Insights into the Mechanisms for Cadmium-induced Urothelial Transformation.
    Bin Wu, Xu Jiang, Yapeng Huang, Xiaoling Ying, Haiqing Zhang, Bixia Liu, Zhuo Li, Dengfeng Qi, Weidong Ji, Xingming Cai.
      Objective This study aimed to investigate the mechanisms underlying Cd-induced urothelial transformation, using multi-omics analyses (transcriptome, epitranscriptome, and proteome). Methods Transcriptomics analysis was performed to estimate the expression of genes, methylated RNA immunoprecipitation sequencing analysis was used to detect m6A modification, while proteomics analysis was used to identify differentially expressed proteins. Differentially expressed genes (DEGs) were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Results A total of 9491 DEGs, 711 differentially expressed proteins, and 633 differentially m6A modified genes between Cd-transformed cells and control cells were identified. The regulation of most genes varied at different omics layers. The three omics data shared 57 genes, and these genes were enriched in response to DNA damage stimulus and cell proliferation. Interestingly, 13 genes, most of which are related to the onset or progression of cancer, were shared by the m6A and proteomics data, but not the transcriptome data. This suggested that m6A modification is crucial for post-transcriptional regulation related to Cd2+ -induced malignant transformation. Conclusion Our multi-omics analysis provided a comprehensive reference map of gene activity and revealed m6A signaling pathways crucial for Cd2+ carcinogenesis.
    Keywords:  Cadmium; Carcinogenesis; Proteomic; RNA sequencing; m6A
    DOI:  https://doi.org/10.1080/1354750X.2021.1913513
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