bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021‒01‒24
eleven papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics


  1. EMBO J. 2021 Jan 20. e105977
    He PC, He C.
      RNA carries a diverse array of chemical modifications that play important roles in the regulation of gene expression. N6 -methyladenosine (m6 A), installed onto mRNA by the METTL3/METTL14 methyltransferase complex, is the most prevalent mRNA modification. m6 A methylation regulates gene expression by influencing numerous aspects of mRNA metabolism, including pre-mRNA processing, nuclear export, decay, and translation. The importance of m6 A methylation as a mode of post-transcriptional gene expression regulation is evident in the crucial roles m6 A-mediated gene regulation plays in numerous physiological and pathophysiological processes. Here, we review current knowledge on the mechanisms by which m6 A exerts its functions and discuss recent advances that underscore the multifaceted role of m6 A in the regulation of gene expression. We highlight advances in our understanding of the regulation of m6 A deposition on mRNA and its context-dependent effects on mRNA decay and translation, the role of m6 A methylation of non-coding chromosomal-associated RNA species in regulating transcription, and the activities of the RNA demethylase FTO on diverse substrates. We also discuss emerging evidence for the therapeutic potential of targeting m6 A regulators in disease.
    Keywords:  RNA modifications; epitranscriptome; gene expression; m6A methylation; mRNA
    DOI:  https://doi.org/10.15252/embj.2020105977
  2. Theranostics. 2021 ;11(6): 2581-2593
    Li J, Liang L, Yang Y, Li X, Ma Y.
      Colorectal cancer (CRC) is one of the most prevalent cancers and one of the leading causes of cancer death. Recent studies have provided evidence that N6-methyladenosine (m6A), the most abundant RNA modifications in eukaryote, performs many functions in RNA metabolism including translation, splicing, storage, trafficking and degradation. Aberrant regulation of m6A modification in mRNAs and noncoding RNAs found in CRC tissues is crucial for cancer formation, progression, invasion and metastasis. Further, m6A regulators and m6A-related RNAs may become promising biomarkers, prognosis predictors as well as therapeutic targets. Here, we review the biological and clinical roles of m6A modification in CRC, and discuss the potential of m6A in clinical translation.
    Keywords:  RNA modification; cancer progression; cancer treatment; colorectal cancer; m6A
    DOI:  https://doi.org/10.7150/thno.52366
  3. Theranostics. 2021 ;11(6): 3000-3016
    Han Z, Wang X, Xu Z, Cao Y, Gong R, Yu Y, Yu Y, Guo X, Liu S, Yu M, Ma W, Zhao Y, Xu J, Li X, Li S, Xu Y, Song R, Xu B, Yang F, Bamba D, Sukhareva N, Lei H, Gao M, Zhang W, Zagidullin N, Zhang Y, Yang B, Pan Z, Cai B.
      N6-methyladenosine (m6A) RNA modification, a dynamic and reversible process, is essential for tissue development and pathogenesis. However, the potential involvement of m6A in the regulation of cardiomyocyte (CM) proliferation and cardiac regeneration remains unclear. In this study, we aimed to investigate the essential role of m6A modification in heart regeneration during postnatal and adult injury. Methods and results: In this study, we identified the downregulation of m6A demethylase ALKBH5, an m6A "eraser" that is responsible for increased m6A methylation, in the heart after birth. Notably, ALKBH5 knockout mice exhibited decreased cardiac regenerative ability and heart function after neonatal apex resection. Conversely, forced expression of ALKBH5 via adeno-associated virus-9 (AAV9) delivery markedly reduced the infarct size, restored cardiac function and promoted CM proliferation after myocardial infarction in juvenile (7 days old) and adult (8-weeks old) mice. Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). The modulation of ALKBH5 and YTHDF1 expression in human induced pluripotent stem cell-derived cardiomyocytes consistently yielded similar results. Conclusion: Taken together, our findings highlight the vital role of the ALKBH5-m6A-YTHDF1-YAP axis in the regulation of CMs to re-enter the cell cycle. This finding suggests a novel potential therapeutic strategy for cardiac regeneration.
    Keywords:  ALKBH5; Heart regeneration; cardiomyocyte proliferation; m6A; myocardial infarction
    DOI:  https://doi.org/10.7150/thno.47354
  4. Am J Respir Crit Care Med. 2021 Jan 19.
    Hu L, Wang J, Huang H, Yu Y, Ding J, Yu Y, Li K, Wei D, Ye Q, Wang F, Shen B, Chen J, Fulton DJR, Chen F.
      RATIONALE: Posttranscriptional modifications are implicated in vascular remodeling of pulmonary hypertension (PH). N6-methyladenosine (m6A) is an abundant RNA modification that is involved in various biological processes. Whether m6A RNA modification and m6A effector proteins play a role in pulmonary vascular remodeling and PH have not been demonstrated.OBJECTIVES: To determine whether m6A modification and m6A effectors contribute to the pathogenesis of PH.
    METHODS: m6A modification and YTHDF1 expression were measured in human and experimental PH samples. RIP analysis and m6A-sequencing were employed to screen m6A-marked transcripts. Genetic approaches were employed to assess the respective roles of YTHDF1 and MAGED1 in PH. Primary cells isolation and cultivation were utilized for function analysis of pulmonary artery smooth muscle cells (PASMCs).
    MEASUREMENTS AND MAIN RESULTS: Elevated m6A levels and increased YTHDF1 protein expression were found in human and rodent PH samples as well as in hypoxic PASMCs. Deletion of YTHDF1 ameliorated PASMCs proliferation, phenotype switch and PH development both in vivo and in vitro. m6A RIP analysis identified MAGED1 as an m6A-regulated gene in PH and genetic ablation of MAGED1 improved vascular remodeling and hemodynamic parameters in SU5416/Hypoxia mice. YTHDF1 recognized and promoted translation of MAGED1 in an m6A dependent manner which was absent in METTL3 deficient PASMCs. In addition, MAGED1 silencing inhibited hypoxia-induced proliferation of PASMCs through downregulating PCNA.
    CONCLUSIONS: YTHDF1 promotes PASMCs proliferation and PH by enhancing MAGED1 translation. This study identifies the m6A RNA modification as a novel mediator of pathological changes in PASMCs and PH.
    Keywords:  N<sup>6</sup>-methyladenosine; Phenotypic switching; pulmonary artery smooth muscle cells; translation
    DOI:  https://doi.org/10.1164/rccm.202009-3419OC
  5. Mol Cancer. 2021 01 18. 20(1): 18
    Nombela P, Miguel-López B, Blanco S.
      RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances have been made in understanding the functional role of RNA modifications in regulating coding and non-coding RNA processing and function, which in turn thoroughly shape distinct gene expression programmes. They affect diverse biological processes, and the correct deposition of many of these modifications is required for normal development. Alterations of their deposition are implicated in several diseases, including cancer. In this Review, we focus on the occurrence of N6-methyladenosine (m6A), 5-methylcytosine (m5C) and pseudouridine (Ψ) in coding and non-coding RNAs and describe their physiopathological role in cancer. We will highlight the latest insights into the mechanisms of how these posttranscriptional modifications influence tumour development, maintenance, and progression. Finally, we will summarize the latest advances on the development of small molecule inhibitors that target specific writers or erasers to rewind the epitranscriptome of a cancer cell and their therapeutic potential.
    Keywords:  5-methylcytosine; Anti-cancer therapy; Cancer; Epitranscriptome; Inhibitors; Migration; N6-methyladenosine; Proliferation; Pseudouridine; RNA modifications; m5C; m6A; Ψ
    DOI:  https://doi.org/10.1186/s12943-020-01263-w
  6. Mol Cell. 2021 Jan 12. pii: S1097-2765(20)30959-X. [Epub ahead of print]
    Ogawa A, Nagiri C, Shihoya W, Inoue A, Kawakami K, Hiratsuka S, Aoki J, Ito Y, Suzuki T, Suzuki T, Inoue T, Nureki O, Tanihara H, Tomizawa K, Wei FY.
      About 150 post-transcriptional RNA modifications have been identified in all kingdoms of life. During RNA catabolism, most modified nucleosides are resistant to degradation and are released into the extracellular space. In this study, we explored the physiological role of these extracellular modified nucleosides and found that N6-methyladenosine (m6A), widely recognized as an epigenetic mark in RNA, acts as a ligand for the human adenosine A3 receptor, for which it has greater affinity than unmodified adenosine. We used structural modeling to define the amino acids required for specific binding of m6A to the human A3 receptor. We also demonstrated that m6A was dynamically released in response to cytotoxic stimuli and facilitated type I allergy in vivo. Our findings implicate m6A as a signaling molecule capable of activating G protein-coupled receptors (GPCRs) and triggering pathophysiological responses, a previously unreported property of RNA modifications.
    Keywords:  N6-methyladenosine; RNA catabolism; RNA modification; adenosine; adenosine A3 receptor; extracellular modified nucleosides; signaling molecule
    DOI:  https://doi.org/10.1016/j.molcel.2020.12.038
  7. Arch Toxicol. 2021 Jan 21.
    Ying P, Li Y, Yang N, Wang X, Wang H, He H, Li B, Peng X, Zou D, Zhu Y, Zhong R, Miao X, Tian J, Chang J.
      N6-Methyladenosine (m6A) is the most prevalent modification of RNA in eukaryotes, and is associated with many cellular processes and even the development of cancers. We hypothesized that single-nucleotide polymorphisms (SNPs) in m6A modification genes, including its "writers", "erasers" and "readers", might affect the m6A functions and associate with the susceptibility to pancreatic ductal adenocarcinoma (PDAC). We first conducted a two-stage case-control study in Chinese population to interrogate all SNPs in 22 m6A modification genes. In the discovery stage, a total of 2735 SNPs were genotyped in 980 patients and 1991 controls. Then, the promising SNP was replicated in another independent population consisting of 858 cases and 2084 controls. As a result, we found the rs7495 in 3'UTR of hnRNPC was significantly associated with increased risk of PDAC in both stages (combined odds ratio = 1.22, 95% confidence interval = 1.12-1.32, P = 2.39 × 10-6). To further reveal the biological function of rs7495 and hnRNPC, we performed a series of biochemical experiments. Luciferase reporter assays indicated that rs7495G allele promoted hnRNPC expression through disrupting a putative binding site for has-miR-183-3p. Cell viability assay demonstrated that knockdown of hnRNPC suppressed the proliferation of PDAC cells. RNA-seq analysis suggested that as an m6A "reader", hnRNPC played an important role in RNA biological processes. In conclusion, our findings elucidated that rs7495G could confer higher risk of PDAC via promoting the expression of hnRNPC through a miRNA-mediated manner. These results provided a novel insight into the critical role of m6A modification in tumorigenesis.
    Keywords:  Genetic variant; N6-Methyladenosine; Pancreatic ductal adenocarcinoma; hnRNPC
    DOI:  https://doi.org/10.1007/s00204-021-02978-5
  8. Aging (Albany NY). 2021 Jan 10. 12
    Song W, Yang K, Luo J, Gao Z, Gao Y.
      N6-methyladenosine refers to a methylation of adenosine base at the 6th nitrogen position, which is the dominant methylation modification in both message and non-coding RNAs. Dysregulation of RNA m6A methylation causes tumorigenesis in humans. The key N6-methyladenosine demethylase fat-mass and obesity-associated protein (FTO) is negatively correlated with the overall survival of bladder cancer patients, but the underlying mechanism remains poorly understood. In this study, we demonstrated that the post-translational deubiquitination by USP18 up-regulates the protein but not mRNA of FTO in bladder cancer tissues and cells. As a result, FTO decreased N6-methyladenosine methylation level in PYCR1 through its demethylase enzymatic activity and stabilized PYCR1 transcript to promote bladder cancer initiation and progression. Our work shows the importance of N6-methyladenosine RNA modification in bladder cancer development, and highlights UPS18/FTO/PYCR1 signaling network as potential therapeutic targets of bladder cancer.
    Keywords:  FTO; N6-methyladenosine; bladder cancer; m6A; methylation
    DOI:  https://doi.org/10.18632/aging.202359
  9. EMBO J. 2021 Jan 18. e106309
    Wang Z, Pan Z, Adhikari S, Harada BT, Shen L, Yuan W, Abeywardana T, Al-Hadid Q, Stark JM, He C, Lin L, Yang Y.
      The N6-methyladenosine (m6 A) RNA modification serves crucial functions in RNA metabolism; however, the molecular mechanisms underlying the regulation of m6 A are not well understood. Here, we establish arginine methylation of METTL14, a component of the m6 A methyltransferase complex, as a novel pathway that controls m6 A deposition in mammalian cells. Specifically, protein arginine methyltransferase 1 (PRMT1) interacts with, and methylates the intrinsically disordered C terminus of METTL14, which promotes its interaction with RNA substrates, enhances its RNA methylation activity, and is crucial for its interaction with RNA polymerase II (RNAPII). Mouse embryonic stem cells (mESCs) expressing arginine methylation-deficient METTL14 exhibit significantly reduced global m6 A levels. Transcriptome-wide m6 A analysis identified 1,701 METTL14 arginine methylation-dependent m6 A sites located in 1,290 genes involved in various cellular processes, including stem cell maintenance and DNA repair. These arginine methylation-dependent m6 A sites are associated with enhanced translation of genes essential for the repair of DNA interstrand crosslinks; thus, METTL14 arginine methylation-deficient mESCs are hypersensitive to DNA crosslinking agents. Collectively, these findings reveal important aspects of m6 A regulation and new functions of arginine methylation in RNA metabolism.
    Keywords:  DNA repair; PRMT1; RGG motif; RNA m6A methylation; arginine methylation
    DOI:  https://doi.org/10.15252/embj.2020106309
  10. J Chem Theory Comput. 2021 Jan 20.
    Li Y, Bedi RK, Wiedmer L, Sun X, Huang D, Caflisch A.
      N6-Methyladenosine (m6A) is the most frequent modification in eukaryotic messenger RNA (mRNA) and its cellular processing and functions are regulated by the reader proteins YTHDCs and YTHDFs. However, the mechanism of m6A recognition by the reader proteins is still elusive. Here, we investigate this recognition process by combining atomistic simulations, site-directed mutagenesis, and biophysical experiments using YTHDC1 as a model. We find that the N6 methyl group of m6A contributes to the binding through its specific interactions with an aromatic cage (formed by Trp377 and Trp428) and also by favoring the association-prone conformation of m6A-containing RNA in solution. The m6A binding site dynamically equilibrates between multiple metastable conformations with four residues being involved in the regulation of m6A binding (Trp428, Met438, Ser378, and Thr379). Trp428 switches between two conformational states to build and dismantle the aromatic cage. Interestingly, mutating Met438 and Ser378 to alanine does not alter m6A binding to the protein but significantly redistributes the binding enthalpy and entropy terms, i.e., enthalpy-entropy compensation. Such compensation is reasoned by different entropy-enthalpy transduction associated with both conformational changes of the wild-type and mutant proteins and the redistribution of water molecules. In contrast, the point mutant Thr379Val significantly changes the thermal stability and binding capability of YTHDC1 to its natural ligand. Additionally, thermodynamic analysis and free energy calculations shed light on the role of a structural water molecule that synergistically binds to YTHDC1 with m6A and acts as the hub of a hydrogen-bond network. Taken together, the experimental data and simulation results may accelerate the discovery of chemical probes, m6A-editing tools, and drug candidates against reader proteins.
    DOI:  https://doi.org/10.1021/acs.jctc.0c01136
  11. Development. 2021 Jan 18. pii: dev.188276. [Epub ahead of print]
    Ulmke PA, Xie Y, Sokpor G, Pham L, Shomroni O, Berulava T, Rosenbusch J, Basu U, Fischer A, Nguyen HP, Staiger JF, Tuoc T.
      Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contribute to brain development is largely unknown. Here, we show that Exosc10, an RNA exonuclease subunit of the RNA exosome complex, is indispensable for forebrain development. We report that cortical cells undergo overt apoptosis culminating in cortical agenesis upon conditional deletion of Exosc10 in mouse cortex. Mechanistically, Exosc10 directly binds and degrades transcripts of the P53 signaling-related genes such as Aen and Bbc3. Overall, our findings suggest a crucial role of Exosc10 in suppressing P53 pathway in which the rapid turnover of the apoptosis-effectors Aen and Bbc3 mRNAs is essential for cell survival and normal cortical histogenesis.
    Keywords:  Aen and Bbc3; Apoptosis; Cortical developmen; Exosc10; Exosome complex; P53 pathway; RNA decay
    DOI:  https://doi.org/10.1242/dev.188276