bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021‒08‒01
sixteen papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics

  1. Front Genet. 2021 ;12 671179
      N6-methyladenosine (m6A) RNA methylation regulators play an important role in the occurrence and development of tumors. Here, we aimed to identify the potential roles of m6A RNA methylation regulators in immune infiltrates of ovarian cancer. We obtained two distinct m6A patterns (m6Acluster.A and m6Acluster.B) based on the expression levels of all 21 m6A RNA methylation regulators from The Cancer Genome Atlas (TCGA) database using a consensus clustering algorithm. Differential analysis of m6Acluster.A and m6Acluster.B identified 196 m6A-related genes. We further validated the m6A regulation mechanism based on the 196 m6A-related genes using another consensus clustering algorithm. Considering individual differences, principal component analysis algorithms were used to calculate an m6A score for each sample in order to quantify the m6A patterns. A low m6A score was associated with immune activation and enhanced response to immune checkpoint inhibitors, whereas a high m6A score was associated with tumor progression. Finally, we successfully verified the correlation between m6A regulators and immune microenvironment in OC using our microarray analysis data. In summary, m6A regulators play non-negligible roles in immune infiltrates of ovarian cancer. Our investigation of m6A patterns may help to guide future immunotherapy strategies for advanced ovarian cancer.
    Keywords:  consensus clustering algorithm; immune cell infiltrates; immune checkpoint inhibitors; m6A RNA methylation regulators; ovarian cancer
  2. J Transl Med. 2021 Jul 30. 19(1): 323
      BACKGROUND: Pancreatic cancer is a fatal malignancy of the digestive system and the 5-year survival rate remains low. Therefore, new molecular therapeutic targets are required to improve treatments, prognosis, and the survival of patients. N6-methyladenosine (m6A) is the most prevalent reversible methylation in mammalian messenger RNA (mRNA) and has critical roles in the tumorigenesis and metastasis of various malignancies. However, the role of m6A in pancreatic cancer is still unclear. Exploring genetic alterations and functional networks of m6A regulators in pancreatic cancer may provide new strategies for its treatment.METHODS: In this study, we used data from the Cancer Genome Atlas (TCGA) database and other public databases through cBioPortal, LinkedOmics, UALCAN, GEPIA, STRING, and the database for annotation, visualization, and integrated discovery (DAVID) to systematically analyze the molecular alterations and functions of 20 main m6A regulators in pancreatic cancer.
    RESULTS: We found that m6A regulators had widespread genetic alterations, and that their expression levels were significantly correlated with pancreatic cancer malignancy. Moreover, m6A regulators were associated with the prognosis of pancreatic cancer patients.
    CONCLUSIONS: m6A regulators play a crucial part in the occurrence and development of pancreatic cancer. Our study will guide further studies of m6A RNA modification in pancreatic cancer and could potentially provide new strategies for pancreatic cancer treatment.
    Keywords:  Genetic alterations; N6-methyladenosine (m6A); Pancreatic cancer; Survival; m6A RNA methylation regulators
  3. Cell Biosci. 2021 Jul 27. 11(1): 147
      Autophagy is a conserved degradation process crucial to maintaining the primary function of cellular and organismal metabolism. Impaired autophagy could develop numerous diseases, including cancer, cardiomyopathy, neurodegenerative disorders, and aging. N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells, and the fate of m6A modified transcripts is controlled by m6A RNA binding proteins. m6A modification influences mRNA alternative splicing, stability, translation, and subcellular localization. Intriguingly, recent studies show that m6A RNA methylation could alter the expression of essential autophagy-related (ATG) genes and influence the autophagy function. Thus, both m6A modification and autophagy could play a crucial role in the onset and progression of various human diseases. In this review, we summarize the latest studies describing the impact of m6A modification in autophagy regulation and discuss the role of m6A modification-autophagy axis in different human diseases, including obesity, heart disease, azoospermatism or oligospermatism, intervertebral disc degeneration, and cancer. The comprehensive understanding of the m6A modification and autophagy interplay may help in interpreting their impact on human diseases and may aid in devising future therapeutic strategies.
    Keywords:  Autophagy; Azoospermatism; Cancer; Ischemic heart disease; Obesity; RNA methylation; m6A
  4. J Med Virol. 2021 Jul 30.
      N6 -methyladenosine (m6 A) modification is the most common and reversible post-transcriptional modification of RNA in eukaryotes, which is mainly regulated by methyltransferase, demethylase and specific binding protein. The replication of virus and host immune response to virus are affected by m6 A modification. In different kinds of virus, m6 A modification has two completely opposite regulatory functions. This paper reviews the regulatory effects of m6 A modification on different viruses, and provides a reference for studying the regulatory effects of RNA epitranscriptomic modification. This article is protected by copyright. All rights reserved.
    Keywords:  N6-methyladenosine (m6A); regulatory effect; virus
  5. PLoS Biol. 2021 Jul;19(7): e3001292
      Among over 150 distinct RNA modifications, N6-methyladenosine (m6A) and adenosine-to-inosine (A-to-I) RNA editing represent 2 of the most studied modifications on mammalian mRNAs. Although both modifications occur on adenosine residues, knowledge on potential functional crosstalk between these 2 modifications is still limited. Here, we show that the m6A modification promotes expression levels of the ADAR1, which encodes an A-to-I RNA editing enzyme, in response to interferon (IFN) stimulation. We reveal that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) mediates up-regulation of ADAR1; YTHDF1 is a reader protein that can preferentially bind m6A-modified transcripts and promote translation. Knockdown of YTHDF1 reduces the overall levels of IFN-induced A-to-I RNA editing, which consequently activates dsRNA-sensing pathway and increases expression of various IFN-stimulated genes. Physiologically, YTHDF1 deficiency inhibits virus replication in cells through regulating IFN responses. The A-to-I RNA editing activity of ADAR1 plays important roles in the YTHDF1-dependent IFN responses. Therefore, we uncover that m6A and YTHDF1 affect innate immune responses through modulating the ADAR1-mediated A-to-I RNA editing.
  6. PLoS Biol. 2021 Jul;19(7): e3001342
      A new study in PLOS Biology finds that interferon (IFN)-induced adenosine deaminase acting on RNA 1 (ADAR1) mRNA is N6-methyladenosine (m6A) modified to promote its translation, enabling ADAR1 to modify self-double-stranded RNAs (dsRNAs) generated during the IFN response and preventing activation of the melanoma differentiation-associated protein 5 (MDA5)-mediated host antiviral response.
  7. Front Cell Dev Biol. 2021 ;9 651575
      N6-methyladenosine (m6A) is the most prevalent type of RNA modification, and we hypothesized that patterns of m6A-related genes may be useful for estimating risk of lung adenocarcinoma (LUAD). An m6A-related gene set variation score (m6A-GSVS) was generated using RNA-sequencing data from LUAD patients in The Cancer Genome Atlas (TCGA). We investigated the association of m6A-GSVS with stemness, tumor mutational burden (TMB), expression of three immune checkpoints, levels of tumor-infiltrating lymphocytes (TILs), and patient prognosis. We found that m6A-GSVS was higher in LUAD than in healthy lung tissue, and it strongly correlated with stemness and TMB. Activated CD4 + T cells were more numerous in LUAD samples that had higher m6A-GSVS than in those with lower scores. Biological processes and pathways, including "Cell cycle," "DNA replication," and "RNA degradation," were significantly enriched in samples with high scores. Furthermore, m6A-GSVS was an independent prognostic indicator in LUAD. In conclusion, we proposed an m6A-GSVS in LUAD. It is a putative indicator for evaluating the ability to RNA m6A, an independent prognostic indicator and associated with tumor stemness.
    Keywords:  N6-methyladenosine; lung adenocarcinoma; prognostic biomarker; tumor mutational burden; tumor-infiltrating lymphocytes
  8. Cell Death Dis. 2021 Jul 27. 12(8): 744
      Multifunctional N6-methyladenosine (m6A) has been revealed to be an important epigenetic component in various physiological and pathological processes, but its role in female ovarian aging remains unclear. Thus, we demonstrated m6A demethylase FTO downregulation and the ensuing increased m6A in granulosa cells (GCs) of human aged ovaries, while FTO-knockdown GCs showed faster aging-related phenotypes mediated. Using the m6A-RNA-sequence technique (m6A-seq), increased m6A was found in the FOS-mRNA-3'UTR, which is suggested to be an erasing target of FTO that slows the degradation of FOS-mRNA to upregulate FOS expression in GCs, eventually resulting in GC-mediated ovarian aging. FTO acts as a senescence-retarding protein via m6A, and FOS knockdown significantly alleviates the aging of FTO-knockdown GCs. Altogether, the abovementioned results indicate that FTO in GCs retards FOS-dependent ovarian aging, which is a potential diagnostic and therapeutic target against ovarian aging and age-related reproductive diseases.
  9. Cell Death Dis. 2021 Jul 29. 12(8): 750
      Emerging discoveries of dynamic and reversible N6-methyladenosine (m6A) modification on RNA in mammals have revealed the key roles of the modification in human tumorigenesis. As known m6A readers, insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) are upregulated in most cancers and mediates the enhancement of m6A-modified mRNAs stability. However, the mechanisms of IGF2BPs in renal cell cancer (RCC) still remain unclear. Bioinformatic analysis and RT-qPCR were performed to evaluate the expression of IGF2BPs and m6A writer Wilms tumor 1-associating protein (WTAP) in RCC samples and its correlation with patient prognosis. In vitro, in vivo biological assays were performed to investigate the functions of IGF2BPs and WTAP in RCC. Chromatin immunoprecipitation-qPCR (ChIP-qPCR) combined with bioinformatics analysis and following western blot assay, dual-luciferase reporter assays were performed to validate the regulatory relationships between transcription factor (TF) early growth response 2 (EGR2) and potential target genes IGF2BPs. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation-qPCR (MERIP-qPCR), RIP-qPCR, m6A dot blot, and dual-luciferase reporter assays combined with bioinformatics analysis were employed to screen and validate the direct targets of IGF2BPs and WTAP. Here, we showed that early growth response 2 (EGR2) transcription factor could increase IGF2BPs expression in RCC. IGF2BPs in turn regulated sphingosine-1-phosphate receptor 3 (S1PR3) expression in an m6A-dependent manner by enhancing the stability of S1PR3 mRNA. They also promoted kidney tumorigenesis via PI3K/AKT pathway. Furthermore, IGF2BPs and WTAP upregulation predicted poor overall survival in RCC. Our studies showed that the EGR2/IGF2BPs regulatory axis and m6A-dependent regulation of S1PR3-driven RCC tumorigenesis, which enrich the m6A-modulated regulatory network in renal cell cancer. Together, our findings provide new evidence for the role of N6-methyladenosine modification in RCC.
  10. Int J Biol Sci. 2021 ;17(10): 2633-2651
      Lung cancer is one of the most common types of carcinoma worldwide. Cigarette smoking is considered the leading cause of lung cancer. Aberrant expression of several YT521-B homology (YTH) family proteins has been reported to be closely associated with multiple cancer types. The present study aims to evaluate the function and regulatory mechanisms of the N6-methyladenosine (m6A) reader protein YTH domain containing 2 (YTHDC2) by in vitro, in vivo and bioinformatics analyses. The results revealed that YTHDC2 was reduced in lung cancer and cigarette smoke-exposed cells. Notably, bioinformatics and tissue arrays analysis demonstrated that decreased YTHDC2 was highly associated with smoking history, pathological stage, invasion depth, lymph node metastasis and poor outcomes. The in vivo and in vitro studies revealed that YTHDC2 overexpression inhibited the proliferation and migration of lung cancer cells as well as tumor growth in nude mice. Furthermore, YTHDC2 decreased expression was modulated by copy number deletion in lung cancer. Importantly, the cylindromatosis (CYLD)/NF-κB pathways were confirmed as the downstream signaling of YTHDC2, and this axis was mediated by m6A modification. The present results indicated that smoking-related downregulation of YTHDC2 was associated with enhanced proliferation and migration in lung cancer cells, and appeared to be regulated by DNA copy number variation. Importantly, YTHDC2 functions as a tumor suppressor through the CYLD/NF-κB signaling pathway, which is mediated by m6A modification.
    Keywords:  CYLD; NF-κB pathway; YTHDC2; lung cancer; m6A RNA methylation
  11. Oncogene. 2021 Jul 26.
      N6-Methyladenosine (m6A) is the most prevalent epigenetic RNA modification and is vital in regulating malignancies. The roles of m6A modifiers on noncoding RNAs have not been fully investigated in esophageal cancer. By screening all m6A modifiers, ALKBH5 was the most potent member related to patient outcomes and suppressing esophageal cancer malignancy in cell and animal models. It demethylated pri-miR-194-2 and inhibited miR-194-2 biogenesis through an m6A/DGCR8-dependent manner. RAI1, previously considered as a circadian clock transcriptional regulator, was the main target of miR-194-2. It enhanced transcription of Hippo pathway upstream genes by binding to their 3'UTR and suppressed YAP/TAZ nuclear translocation. The ALKBH5/miR-194-2/RAI1 axis was also validated in clinical samples. In addition, the increased malignancy by low ALKBH5 was abolished by the YAP inhibitor verteporfin. Our findings uncover a critical role of ALKBH5 in miRNAs biogenesis and provide novel insight for developing treatment strategies in esophageal cancer.
  12. Front Cell Dev Biol. 2021 ;9 715674
      Previous studies have reported that m6a modification promotes tumor immune escape by affecting tumor microenvironment (TME). Due to the complexity of TME, a single biomarker is insufficient to describe the complex biological characteristics of tumor and its microenvironment. Therefore, it is more meaningful to explore a group of effective biomarkers reflecting different characteristics of cancer to evaluate the biological characteristics of solid tumors. Here, the immune gene CD34/CD276 with different m6A peak was obtained by m6A sequencing (MeRIP-seq) of colon cancer (CRC)clinical samples and combined with MsIgDB database, which was used to perform cluster analysis on TCGA-COAD level 3 data. The CD34/CD276 as a molecular marker for CRC prognosis was confirmed by survival analysis and immunohistochemical assay. Further bioinformatics analysis was carried out to analyze the molecular mechanism of CD34/CD276 affecting the TME through m6a-dependent down-regulation and ultimately promoting immune escape of CRC.
    Keywords:  CD276(B7-H3); CD34; N6-methyladenosine; colon cancer; immune escape
  13. Adv Med Sci. 2021 Jul 22. pii: S1896-1126(21)00038-9. [Epub ahead of print]66(2): 351-358
      PURPOSE: RNA demethylase AlkB homolog 5 (ALKBH5) gene is pivotal in N6-methyladenosine (m6A) modification. Therefore, this study aimed to explore the potential relationship between polymorphisms of ALKBH5 gene and the development of autoimmune thyroid disease (AITD).MATERIAL AND METHODS: A case-control study of 979 AITD patients, including 620 Graves' disease (GD) and 359 Hashimoto's thyroiditis (HT), and 732 normal controls of the Chinese Han population was performed using high-throughput sequencing (HiSeq) genotyping method for detecting 5 variants in ALKBH5 gene (rs12936694, rs2124370, rs4925144, rs8068517, and rs9913266). In addition, the associations between ALKBH5 single nucleotide polymorphisms (SNPs) and clinical phenotypes of AITD were investigated.
    RESULTS: Compared to normal controls, rs9913266 displayed significant differences in allele and genotype distributions in AITD and GD. rs12936694 also showed significantly different frequencies of alleles in AITD and GD. The link of these 2 loci polymorprhisms to AITD and GD also existed after adjusting for age and gender. When stratified by sex, the minor allele of rs9913266 was associated with the risk of female AITD and HT development before and after adjusting for age and gender. There was a significant association between rs8068517 locus and GD in females after adjusting for the confounders. Finally, we observed significant correlations of haplotypes CGACA and CAGCG to the susceptibility of AITD and GD.
    CONCLUSIONS: Our results provided evidence of association of polymorphisms in ALKBH5 gene with AITD, GD, and HT patients, and hence ALKBH5 might be the candidate gene for susceptibility to AITD.
    Keywords:  ALKBH5; Autoimmune thyroid disease (AITD); Graves' disease; Hashimoto's thyroiditis; Polymorphism
  14. J Cell Mol Med. 2021 Jul 27.
      YTH domain containing 2 (YTHDC2) is the largest N6-Methyladenosine (m6 A) binding protein of the YTH protein family and the only member containing ATP-dependent RNA helicase activity. For further analysing its biological role in epigenetic modification, we comprehensively explored YTHDC2 from gene expression, genetic alteration, protein-protein interaction (PPI) network, immune infiltration, diagnostic value and prognostic value in pan-cancer, using a series of databases and bioinformatic tools. We found that YTHDC2 with Missense mutation could cause a different prognosis in uterine corpus endometrial carcinoma (UCEC), and its different methylation level could lead to a totally various prognosis in adrenocortical carcinoma (ACC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), lung squamous cell carcinoma (LUSC) and UCEC. The main molecular mechanisms of YTHDC2 focused on catalytic activity, helicase activity, snRNA binding, spliceosome and mRNA surveillance. Additionally, YTHDC2 was notably correlated with tumour immune infiltration. Moreover, YTHDC2 had a high diagnostic value for seven cancer types and a prognostic value for brain lower grade glioma (LGG), rectum adenocarcinoma (READ) and skin cutaneous melanoma (SKCM). Collectively, YTHDC2 plays a significant role in epigenetic modification and immune infiltration and maybe a potential biomarker for diagnosis and prognosis in certain cancers.
    Keywords:  YTHDC2; diagnosis; immune infiltration; m6A; prognosis
  15. Cancer Sci. 2021 Jul 26.
      BACKGROUND/AIMS: Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is a post-transcriptional regulatory factor that has been implicated in the development of cancer. Herein, this study was performed to examine the possible role of of IGF2BP2 in colorectal cancer (CRC) and its underlying mechanism.METHODS: First, the expression patterns of IGF2BP2, YAP, and ErbB2 were detected in clinical tissue samples from CRC patients and CRC cell lines. In addition, cell proliferation, migration, invasion and apoptosis were measured and recorded. Enrichment of TEAD4 in the ErbB2 promoter region was measured. Furthermore, IGF2BP2 binding to m6A-modified YAP mRNA was determined using Me-RIP assay with anti-IGF2BP2 antibody. Lastly, a xenograft tumor mouse model was established to substantiate in vitro findings.
    RESULTS: IGF2BP2, YAP, and ErbB2 were highly-expressed in CRC tissues and cell lines. In addition, IGF2BP2 was found to be bind to m6A-modified YAP mRNA and increased its stability in CRC cells, thus augmenting the proliferation, migration and invasion of CRC cells while reducing their apoptosis. Meanwhile, YAP regulated ErbB2 expression by promoting TEAD4 enrichment in the ErbB2 promoter region. IGF2BP2 up-regulated ErbB2 by stabilizing YAP expression, and thus promoted proliferation, migration and invasion of CRC cells while attenuating their apoptosis. Also, IGF2BP2 promoted tumor formation in nude mice by regulating the YAP/ErbB2 axis.
    CONCLUSION: Overall, our findings indicated that IGF2BP2 may bind to m6A-modified YAP mRNA to promote YAP stability and activate the expression of ErbB2, thus facilitating the progression of CRC.
    Keywords:  Apoptosis; Colorectal cancer; ErbB2; IGF2BP2; Invasion; Migration; Proliferation; YAP; m6A
  16. Cell Death Dis. 2021 Jul 26. 12(8): 737
      Neutrophils are significant compositions of solid tumors and exert distinct functions in different types of tumors. However, the precise role of neutrophils in the progression of breast cancer (BC) is presently unclear. In this study, by investigating the single-cell RNA sequencing data, we identify a new neutrophil subset, C5aR1-positive neutrophils, that correlates with tumor progression and poor survival for BC patients. Furthermore, it is discovered that C5aR1-positive neutrophils enhance BC cell glycolysis via upregulating ENO1 expression. Mechanically, C5aR1-positive neutrophil-secreted IL1β and TNFα cooperatively activate ERK1/2 signaling, which phosphorylates WTAP at serine341 and thereby stabilizes WTAP protein. The stabilization of WTAP further promotes RNA m6A methylation of ENO1, impacting the glycolytic activity of BC cells. Importantly, C5aR1-positive neutrophils also promote breast cancer growth in vivo, and this effect is abolished by WTAP silencing. In clinical BC samples, increased C5aR1-positive neutrophils correlate with elevated IL1β, TNFα, and ENO1 expression. A high co-expression of C5aR1-positive neutrophil gene signature and ENO1 predicts worse prognosis of BC patients compared with a low co-expression. Collectively, our study reveals a novel subset of C5aR1-positive neutrophils that induces breast cancer glycolysis via increasing ERK1/2-WTAP-dependent m6A methylation of ENO1. These findings support the potential for exploration of C5aR1-positive neutrophils as a therapeutic target in breast cancer.