bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–05–16
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Importance of N6-methyladenosine RNA modification in lung cancer (Review).
  2. Funm6AViewer: a web server and R package for functional analysis of context-specific m6A RNA methylation.
  3. N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma.
  4. Epigenetic Regulation of m6A Modifications in Obesity.
  5. The potential role of m6A RNA methylation in diabetic retinopathy.
  6. WNT/β-catenin-suppressed FTO expression increases m6A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis.
  7. Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing.
  8. RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/β-catenin signaling.
  9. The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma.
  1. Mol Clin Oncol. 2021 Jun;14(6): 128
    Importance of N6-methyladenosine RNA modification in lung cancer (Review).
    Yueyang Wang, Xiaoming Su, Mingyao Zhao, Mingchen Xu, Yueqi Chen, Zhengyi Li, Wenyue Zhuang.
      The N6-methyladenosine (m6A) modification is the most common mRNA modification in eukaryotes and exerts biological functions by affecting RNA metabolism. The m6A modification is installed by m6A methyltransferases, removed by demethylases and recognized by m6A-binding proteins. The interaction between these three elements maintains the dynamic equilibrium of m6A in cells. Accumulating evidence indicates that m6A RNA methylation has a significant impact on RNA metabolism and is involved in the pathogenesis of cancer. Lung cancer is the leading cause of cancer-related deaths worldwide. The treatment options for lung cancer have developed considerably over the past few years; however, the survival rate of patients with lung cancer still remains very low. Although diagnostic methods and targeted therapies have been rapidly developed in recent years, the underlying mechanism and importance of m6A RNA methylation in the pathogenesis of lung cancer remains ambiguous. The current review summarized the biological functions of m6A modification and considers the potential roles of m6A regulators in the occurrence and development of lung cancer.
    Keywords:  N6-methyladenosine; RNA methylation; lung cancer; methyltransferase-like 3; translation
    DOI:  https://doi.org/10.3892/mco.2021.2290
  2. Bioinformatics. 2021 May 11. pii: btab362. [Epub ahead of print]
    Funm6AViewer: a web server and R package for functional analysis of context-specific m6A RNA methylation.
    Song-Yao Zhang, Shao-Wu Zhang, Yujiao Tang, Xiao-Nan Fan, Jia Meng.
       MOTIVATION: N6-methyladenosine (m6A) is the most abundant mammalian mRNA methylation with versatile functions. To date, although a number of bioinformatics tools have been developed for location discovery of m6A modification, functional understanding is still quite limited. As the focus of RNA epigenetics gradually shifts from site discovery to functional studies, there is an urgent need for user-friendly tools to identify and explore the functional relevance of context-specific m6A methylation to gain insights into the epitranscriptome layer of gene expression regulation.
    RESULTS: We introduced here Funm6AViewer, a novel platform to identify, prioritize, and visualize the functional gene interaction networks mediated by dynamic m6A RNA methylation unveiled from a case control study. By taking the differential RNA methylation (DM) data and differential gene expression (DE) data, both of which can be inferred from the widely used MeRIP-seq data, as the inputs, Funm6AViewer enables a series of analysis, including: (1) examining the distribution of differential m6A sites, (2) prioritizing the genes mediated by dynamic m6A methylation, and (3) characterizing functionally the gene regulatory networks mediated by condition-specific m6A RNA methylation. Funm6AViewer should effectively facilitate the understanding of the epitranscriptome circuitry mediated by this reversible RNA modification. Funm6AViewer is available both as a convenient web server (https://www.xjtlu.edu.cn/biologicalsciences/funm6aviewer) with graphical interface and as an independent R package (https://github.com/NWPU-903PR/Funm6AViewer) for local usage.
    SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
    DOI:  https://doi.org/10.1093/bioinformatics/btab362
  3. Oncogene. 2021 May 10.
    N6-methyladenosine demethyltransferase FTO-mediated autophagy in malignant development of oral squamous cell carcinoma.
    Fang Wang, Yan Liao, Ming Zhang, Yue Zhu, Wenjin Wang, Hongshi Cai, Jianfeng Liang, Fan Song, Chen Hou, Shuojin Huang, Yadong Zhang, Cheng Wang, Jinsong Hou.
      N6-methyladenosine (m6A) is the most abundant internal mRNA modification in eukaryotes and plays an important role in tumorigenesis. However, the underlying mechanism remains largely unclear. Here, we established a cell model of rapamycin-induced autophagy to screen m6A-modifying enzymes. We found that m6A demethylase fat mass and obesity-associated protein (FTO) plays a key role in regulating autophagy and tumorigenesis by targeting the gene encoding eukaryotic translation initiation factor gamma 1 (eIF4G1) in oral squamous cell carcinoma (OSCC). Knocked down of FTO expression in OSCC cell lines, resulting in downregulation of eIF4G1 along with enhanced autophagic flux and inhibition of tumorigenesis. Rapamycin inhibited FTO activity, and directly targeted eIF4G1 transcripts and mediated their expression in an m6A-dependent manner. Dual-luciferase reporter and mutagenesis assays confirmed that YTH N6-methyladenosine RNA-binding protein 2 (YTHDF2) targets eIF4G1. Conclusively, after FTO silencing, YTHDF2 captured eIF4G1 transcripts containing m6A, resulting in mRNA degradation and decreased expression of eIF4G1 protein, thereby promoting autophagy and reducing tumor occurrence. Therefore, rapamycin may regulate m6A levels, determining the autophagic flux of OSCC, thereby affecting the biological characteristics of cancer cells. This insight expands our understanding of the crosstalk between autophagy and RNA methylation in tumorigenesis, which is essential for therapeutic strategy development for OSCC.
    DOI:  https://doi.org/10.1038/s41388-021-01820-7
  4. J Diabetes Investig. 2021 May 12.
    Epigenetic Regulation of m6A Modifications in Obesity.
    Mingli Sun, Xinan Zhang.
      Obesity is a serious health issue in the world and is related to a higher risk of suffering metabolic diseases. Understanding the molecular basis of obesity is critical to identify new targets to treat obesity and obesity-associated metabolic diseases. N6-methyladenosine (m6A) modification is the most common form of RNA modification which has attracted the increasing interest of researchers in recent years, as it is reported that m6A has vital functions in diseases and everyday life activities. Recent studies indicated m6A modification was decreased in obese adipose tissue and appeared to play a regulatory role in many obesity-associated biological processes, including adipogenesis，lipid metabolism，and insulin resistance. In this review, we discussed the emerging advances in m6A modification in obesity to provide a novel therapeutic strategy for fighting against obesity.
    Keywords:  N6-methyladenosine; Obesity; adipogenesis; therapeutic targets
    DOI:  https://doi.org/10.1111/jdi.13571
  5. Exp Eye Res. 2021 May 09. pii: S0014-4835(21)00182-2. [Epub ahead of print] 108616
    The potential role of m6A RNA methylation in diabetic retinopathy.
    Nidhi Kumari, Aditi Karmakar, Md Maqsood Ahamad Khan, Senthil Kumar Ganesan.
      Diabetic retinopathy (DR), a major microvascular complication of diabetes, affects most diabetic individuals and has become the leading cause of vision loss. Metabolic memory associated with diabetes retains the risk of disease occurrence even after the termination of glycemic insult. Further, various limitations associated with its current diagnostic and treatment strategies like unavailability of early diagnostic and treatment methods, variation in treatment response from patient to patient, and cost-effectiveness have driven the need to find alternative solutions. Post-transcriptional epigenetic modification of RNA mainly, N6-methyladenosine (m6A), is an emerging concept in the scientific community. It has an indispensable effect in various physiological and pathological conditions. m6A mediates its effect through the various reader, writer, and eraser proteins. Recent studies have shown the impact of m6A RNA modification on various disease conditions, including diabetes, but its role in diabetic retinopathy is still unclear. However, change in m6A levels has been observed in various prime aggravators of DR pathogenesis, such as inflammation, oxidative stress, and angiogenesis. Further, various non-coding RNAs like microRNA, lncRNA, and circRNA are also associated with DR, and m6A has been shown to affect all these non-coding RNAs. This review is concerned with the possible mechanisms through which alteration in m6A modification of RNA can participate in the DR progression and pathogenesis and its expected role in metabolic memory phenomena.
    Keywords:  Diabetic retinopathy; Epitranscriptomics; Metabolic memory; m6A RNA methylation
    DOI:  https://doi.org/10.1016/j.exer.2021.108616
  6. Cell Death Dis. 2021 May 08. 12(5): 462
    WNT/β-catenin-suppressed FTO expression increases m6A of c-Myc mRNA to promote tumor cell glycolysis and tumorigenesis.
    Xueying Yang, Fei Shao, Dong Guo, Wei Wang, Juhong Wang, Rongxuan Zhu, Yibo Gao, Jie He, Zhimin Lu.
      FTO removes the N6-methyladenosine (m6A) modification from genes and plays a critical role in cancer development. However, the mechanisms underlying the regulation of FTO and its subsequent impact on the regulation of the epitranscriptome remain to be further elucidated. Here, we demonstrate that FTO expression is downregulated and inversely correlated with poor survival of lung adenocarcinoma patients. Mechanistically, Wnt signaling induces the binding of EZH2 to β-catenin. This protein complex binds to the LEF/TCF-binding elements at the promoter region of FTO, where EZH2 enhances H3K27me3 and inhibits FTO expression. Downregulated FTO expression substantially enhances the m6A levels in the mRNAs of a large number of genes in critical pathways, particularly metabolic pathway genes, such as MYC. Enhanced m6A levels on MYC mRNA recruit YTHDF1 binding, which promotes MYC mRNA translation and a subsequent increase in glycolysis and proliferation of tumor cells and tumorigenesis. Our findings uncovered a critical mechanism of epitranscriptome regulation by Wnt/β-catenin-mediated FTO downregulation and underscored the role of m6A modifications of MYC mRNA in regulating tumor cell glycolysis and growth.
    DOI:  https://doi.org/10.1038/s41419-021-03739-z
  7. Nat Biotechnol. 2021 May 13.
    Quantitative profiling of pseudouridylation dynamics in native RNAs with nanopore sequencing.
    Oguzhan Begik, Morghan C Lucas, Leszek P Pryszcz, Jose Miguel Ramirez, Rebeca Medina, Ivan Milenkovic, Sonia Cruciani, Huanle Liu, Helaine Graziele Santos Vieira, Aldema Sas-Chen, John S Mattick, Schraga Schwartz, Eva Maria Novoa.
      Nanopore RNA sequencing shows promise as a method for discriminating and identifying different RNA modifications in native RNA. Expanding on the ability of nanopore sequencing to detect N6-methyladenosine, we show that other modifications, in particular pseudouridine (Ψ) and 2'-O-methylation (Nm), also result in characteristic base-calling 'error' signatures in the nanopore data. Focusing on Ψ modification sites, we detected known and uncovered previously unreported Ψ sites in mRNAs, non-coding RNAs and rRNAs, including a Pus4-dependent Ψ modification in yeast mitochondrial rRNA. To explore the dynamics of pseudouridylation, we treated yeast cells with oxidative, cold and heat stresses and detected heat-sensitive Ψ-modified sites in small nuclear RNAs, small nucleolar RNAs and mRNAs. Finally, we developed a software, nanoRMS, that estimates per-site modification stoichiometries by identifying single-molecule reads with altered current intensity and trace profiles. This work demonstrates that Nm and Ψ RNA modifications can be detected in cellular RNAs and that their modification stoichiometry can be quantified by nanopore sequencing of native RNA.
    DOI:  https://doi.org/10.1038/s41587-021-00915-6
  8. Cell Death Dis. 2021 May 13. 12(5): 479
    RNA m6A reader YTHDF2 facilitates lung adenocarcinoma cell proliferation and metastasis by targeting the AXIN1/Wnt/β-catenin signaling.
    Yin Li, Hao Sheng, Feng Ma, Qiang Wu, Jianfang Huang, Qiang Chen, Lianghe Sheng, Xinghai Zhu, Xiaoxi Zhu, Meng Xu.
      Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related deaths worldwide. YTHDF2 is a reader of N6-methyladenosine (m6A) on RNA and plays a critical role in the initiation and propagation of myeloid leukemia; however, whether YTHDF2 controls the development of LUAD remains to be explored. Here, we found that YTHDF2 was significantly upregulated in LUAD compared with paracancerous normal tissues, and YTHDF2 knockdown drastically inhibited, while its overexpression promoted, cell growth, colony formation and migration of LUAD cells in vitro. In addition, YTHDF2 knockdown significantly inhibited tumorigenesis in a murine tumor xenograft model. Through the integrative analysis of RNA-seq, m6A-seq, CLIP-seq, and RIP-seq datasets, we identified a set of potential direct targets of YTHDF2 in LUAD, among which we confirmed AXIN1, which encodes a negative regulator of the Wnt/β-catenin signaling, as a direct target of YTHDF2. YTHDF2 promoted AXIN1 mRNA decay and subsequently activated the Wnt/β-catenin signaling. Knockout of AXIN1 sufficiently rescued the inhibitory effect of YTHDF2 depletion on lung cancer cell proliferation, colony-formation, and migration. These results revealed YTHDF2 to be a contributor of LUAD development acting through the upregulation of the AXIN1/Wnt/β-catenin signaling, which can be a potential therapeutic target for LUAD.
    DOI:  https://doi.org/10.1038/s41419-021-03763-z
  9. Transl Androl Urol. 2021 Apr;10(4): 1711-1722
    The m6A methyltransferase METTL3 regulates autophagy and sensitivity to cisplatin by targeting ATG5 in seminoma.
    Hanfei Chen, Yali Xiang, Yinghao Yin, Jingxuan Peng, Dongyi Peng, Dongjie Li, Riko Kitazawa, Yuxin Tang, Jianfu Yang.
       Background: Our previous work shows Autophagy enhanced resistance to cisplatin in seminoma. The expression of the N6-methyladenosine (m6A) methyltransferases METTL3 was significantly increased in the cisplatin-resistant TCam-2 cell line of seminoma. We aimed to investigate the role of m6A methylation in autophagy and the chemosensitivity of seminoma cells.
    Methods: Plasmid and siRNA were used to overexpress and knockdown METTL3. Autophagy was detected by western blot and immunofluorescence, respectively. The expression of downstream targets of METTL3 was detected by quantitative real-time PCR (qRT-PCR) and western blot, and the m6A level of them was detected by MeRIP-qPCR. Chemosensitivity of the TCam-2 cell line was identified through MTT assay.
    Results: Upon METTL3 overexpression, autophagy of TCam-2 cell line was enhanced and its sensitivity to cisplatin was decreased. The use of autophagy inhibitors 3-methyladenine (3-MA) could reverse the protective effect of METTL3 on TCam-2 cells. We found that the up-regulation of METTL3 could increase the m6A modification level of ATG5 transcript, thus increased expression of ATG5. Moreover, knockdown of ATG5 reduced METTL3-induced autophagy, suggesting that ATG5 was a potential target for METTL3 to promote autophagy.
    Conclusions: In summary, our research unveiled the unique mechanism by which m6A methylation regulates autophagy and chemosensitivity of the TCam-2 cell line and METTL3 was a potential target to overcome the cisplatin resistance of seminoma.
    Keywords:  METTL3; Seminoma; autophagy; chemosensitivity; m6A methylation
    DOI:  https://doi.org/10.21037/tau-20-1411
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