bims-rimeca 2021-02-07 papers

bims-rimeca

Biomed News

on RNA methylation in cancer

Issue of 2021–02–07
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics

Contributions and Prognostic Values of N6-Methyladenosine RNA Methylation Regulators in Hepatocellular Carcinoma.
Resveratrol Attenuates High-Fat Diet Induced Hepatic Lipid Homeostasis Disorder and Decreases m6A RNA Methylation.
Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival.
Non-segmented negative-sense RNA viruses utilize N 6-methyladenosine (m6A) as a common strategy to evade host innate immunity.
Kinase GSK3β functions as a suppressor in colorectal carcinoma through the FTO-mediated MZF1/c-Myc axis.
The role of N6-methyladenosine mRNA in the tumor microenvironment.
Role of Methylation in Pro- and Anti-Cancer Immunity.
The Complexity of TET2 Functions in Pluripotency and Development.

Front Genet. 2020 ;11 614566

Contributions and Prognostic Values of N6-Methyladenosine RNA Methylation Regulators in Hepatocellular Carcinoma.

Li-Wen Qi, Jian-Hui Jia, Chen-Hao Jiang, Jian-Ming Hu.

   Introduction: The methylation at position N6 of adenine is called N6-methyladenosine (m6A). This transcriptional RNA modification exerts a very active and important role in RNA metabolism and in other biological processes. However, the activities of m6A associated with malignant liver hepatocellular carcinoma (LIHC) are unknown and are worthy of study.
Materials and Methods: Using the data of University of California, Santa Cruz (UCSC), the expression of M6A methylation regulators in pan-cancer was evaluated as a screening approach to identify the association of M6A gene expression and 18 cancer types, with a specific focus on LIHC. LIHC datasets of The Cancer Genome Atlas (TCGA) were used to explore the expression of M6A methylation regulators and their clinical significance. Gene Ontology (GO) analysis and Gene Set Enrichment Analysis (GSEA) were used to explore the underlying mechanism based on the evaluation of aberrant expression of m6A methylation regulators.
Results: The expression alterations of m6A-related genes varied across cancer types. In LIHC, we found that in univariate Cox regression analysis, up-regulated m6A modification regulators were associated with worse prognosis, except for ZC3H13. Kaplan-Meier survival curve analysis indicated that higher expression of methyltransferase-like protein 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) genes related to the worse survival rate defined by disease-related survival (DSS), overall survival (OS), progression-free interval (PFI), and disease-free interval (DFI). Up-regulated m6A methylation regulator group (cluster2) obtained by consensus clustering was associated with poor prognosis. A six-gene prognostic signature established using the least absolute shrinkage and selection operator (LASSO) Cox regression algorithm performed better in the early (I + II; T1 + T2) stages than in the late (III + IV; T3 + T4) stages of LIHC. Using the gene signature, we constructed a risk score and found that it was an independent predictive factor for prognosis. Using GSEA, we identified processes involved in DNA damage repair and several biological processes associated with malignant tumors that were closely related to the high-risk group.
Conclusion: In summary, our study identified several genes associated with m6A in LIHC, especially METTL3 and YTHDF1, and confirmed that a risk signature comprised of m6A-related genes was able to forecast prognosis.

Keywords:  METTL3; TCGA; UCSC; YTHDF1; consensus clustering; gene signature; hepatocellular carcinoma

DOI:  https://doi.org/10.3389/fgene.2020.614566
Front Pharmacol. 2020 ;11 568006

Resveratrol Attenuates High-Fat Diet Induced Hepatic Lipid Homeostasis Disorder and Decreases m6A RNA Methylation.

Jiamin Wu, Yi Li, Jiayao Yu, Zhending Gan, Wenyao Wei, Chao Wang, Lili Zhang, Tian Wang, Xiang Zhong.

  Purpose:N6-methyladenosine (m6A) mRNA methylation is affected by dietary factors and associated with lipid metabolism; however, whether the regulatory role of resveratrol in lipid metabolism is involved in m6A mRNA methylation remains unknown. Here, the objective of this study was to investigate the effect of resveratrol on hepatic lipid metabolism and m6A RNA methylation in the liver of mice. Methods: A total of 24 male mice were randomly allocated to LFD (low-fat diet), LFDR (low-fat diet + resveratrol), HFD (high-fat diet), and HFDR (high-fat diet + resveratrol) groups for 12 weeks (n = 6/group). Final body weight of mice was measured before sacrificing. Perirhemtric fat, abdominal and epididymal fat, liver tissues, and serum were collected at sacrifice and analyzed. Briefly, mice phenotype, lipid metabolic index, and m6A modification in the liver were assessed. Results: Compared to the HFD group, dietary resveratrol supplementation reduced the body weight and relative abdominal, epididymal, and perirhemtric fat weight in high-fat-exposed mice; however, resveratrol significantly increased average daily feed intake in mice given HFD. The amounts of serum low-density lipoprotein cholesterol (LDL), liver total cholesterol (TC), and triacylglycerol (TAG) were significantly decreased by resveratrol supplementation. In addition, resveratrol significantly enhanced the levels of peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), cytochrome P450, family 4, subfamily a, polypeptide 10/14 (CYP4A10/14), acyl-CoA oxidase 1 (ACOX1), and fatty acid-binding protein 4 (FABP4) mRNA and inhibited acyl-CoA carboxylase (ACC) mRNA levels in the liver. Furthermore, the resveratrol in HFD increased the transcript levels of methyltransferase like 3 (METTL3), alkB homolog 5 (ALKBH5), fat mass and obesity associated protein (FTO), and YTH domain family 2 (YTHDF2), whereas it decreased the level of YTH domain family 3 (YTHDF3) and m6A abundance in mice liver. Conclusion: The beneficial effect of resveratrol on lipid metabolism disorder under HFD may be due to decrease of m6A RNA methylation and increase of PPARα mRNA, providing mechanistic insights into the function of resveratrol in alleviating the disturbance of lipid metabolism in mice.

Keywords:  N6-methyladenosine RNA methylation; high-fat diet; lipid metabolism; obesity; resveratrol

DOI:  https://doi.org/10.3389/fphar.2020.568006
Int J Mol Sci. 2021 Feb 02. pii: 1474. [Epub ahead of print]22(3):

Analysis of m6A RNA Methylation-Related Genes in Liver Hepatocellular Carcinoma and Their Correlation with Survival.

Yong Li, Dandan Qi, Baoli Zhu, Xin Ye.

  N6-methyladenosine (m6A) modification on RNA plays an important role in tumorigenesis and metastasis, which could change gene expression and even function at multiple levels such as RNA splicing, stability, translocation, and translation. In this study, we aim to conduct a comprehensive analysis on m6A RNA methylation-related genes, including m6A RNA methylation regulators and m6A RNA methylation-modified genes, in liver hepatocellular carcinoma, and their relationship with survival and clinical features. Data, which consist of the expression of widely reported m6A RNA methylation-related genes in liver hepatocellular carcinoma from The Cancer Genome Atlas (TCGA), were analyzed by one-way ANOVA, Univariate Cox regression, a protein-protein interaction network, gene enrichment analysis, feature screening, a risk prognostic model, correlation analysis, and consensus clustering analysis. In total, 405 of the m6A RNA methylation-related genes were found based on one-way ANOVA. Among them, DNA topoisomerase 2-alpha (TOP2A), exodeoxyribonuclease 1 (EXO1), ser-ine/threonine-protein kinase Nek2 (NEK2), baculoviral IAP repeat-containing protein 5 (BIRC5), hyaluronan mediated motility receptor (HMMR), structural maintenance of chromosomes protein 4 (SMC4), bloom syndrome protein (BLM), ca-sein kinase I isoform epsilon (CSNK1E), cytoskeleton-associated protein 5 (CKAP5), and inner centromere protein (INCENP), which were m6A RNA methylation-modified genes, were recognized as the hub genes based on the protein-protein interaction analysis. The risk prognostic model showed that gender, AJCC stage, grade, T, and N were significantly different between the subgroup with the high and low risk groups. The AUC, the evaluation parameter of the prediction model which was built by RandomForest, was 0.7. Furthermore, two subgroups were divided by consensus clustering analysis, in which stage, grade, and T differed. We identified the important genes expressed significantly among two clusters, including uridine-cytidine kinase 2 (UCK2), filensin (BFSP1), tubulin-specific chaperone D (TBCD), histone-lysine N-methyltransferase PRDM16 (PRDM16), phosphorylase b ki-nase regulatory subunit alpha (PHKA2), serine/threonine-protein kinase BRSK2 (BRSK2), Arf-GAP with coiled-coil (ACAP3), general transcription factor 3C polypep-tide 2 (GTF3C2), and guanine nucleotide exchange factor MSS4 (RABIF). In our study, the m6A RNA methylation-related genes in liver hepatocellular carcinoma were analyzed systematically, including the expression, interaction, function, and prognostic values, which provided an important theoretical basis for m6A RNA methylation in liver cancer. The nine important m6A-related genes could be prognostic markers in the survival time of patients.

Keywords:  TCGA; liver cancer; m6A modification; m6A related genes; survival

DOI:  https://doi.org/10.3390/ijms22031474
J Virol. 2021 Feb 03. pii: JVI.01939-20. [Epub ahead of print]

Non-segmented negative-sense RNA viruses utilize N 6-methyladenosine (m6A) as a common strategy to evade host innate immunity.

Mijia Lu, Miaoge Xue, Hai-Tao Wang, Elizabeth L Kairis, Sadeem Ahmad, Jiangbo Wei, Zijie Zhang, Yuexiu Zhang, Youling Gao, Dominique Garcin, Mark E Peeples, Amit Sharma, Sun Hur, Chuan He, Jianrong Li.

N6-methyladenosine (m6A) is the most abundant internal RNA modification catalyzed by host RNA methyltransferases. As obligate intracellular parasites, many viruses acquire m6A methylation in their RNAs. However, the biological functions of viral m6A methylation are poorly understood. Here, we found that viral m6A methylation serves as a molecular marker for host innate immunity to discriminate self from nonself RNA and that this novel biological function of viral m6A methylation is universally conserved in several families in non-segmented negative-sense (NNS) RNA viruses. Using m6A methyltransferase (METTL3)-knockout cells, we produced m6A-deficient virion RNA from the representative members of the families Pneumoviridae, Paramyxoviridae, and Rhabdoviridae and found that these m6A-deficient viral RNAs triggered significantly higher levels of type I interferon compared to the m6A-sufficient viral RNAs, in a RIG-I dependent manner. Reconstitution of the RIG-I pathway revealed that m6A-deficient virion RNA induced higher expression of RIG-I, bound to RIG-I more efficiently, enhanced RIG-I ubiquitination, and facilitated RIG-I conformational rearrangement and oligomerization. Furthermore, the m6A binding protein YTHDF2 is essential for suppression of type I interferon signaling pathway included by virion RNA. Collectively, our results suggest that several families in NNS RNA viruses acquire m6A in viral RNA as a common strategy to evade host innate immunity.IMPORTANCE The non-segmented negative-sense (NNS) RNA viruses share many common replication and gene expression strategies. There is no vaccine or antiviral drugs for many of these viruses. We found that representative members in the families of Pneumoviridae, Paramyxoviridae, and Rhabdoviridae in NNS RNA viruses acquire m6A methylation in their genome and antigenome as a means to escape the recognition by host innate immunity via a RIG-I dependent signaling pathway. Viral RNA lacking m6A methylation induces a significantly higher type I interferon compared to m6A sufficient viral RNA. In addition to uncovering m6A methylation as a common mechanism for many NNS RNA viruses to evade host innate immunity, this study discovered a novel strategy to enhance type I interferon responses, which may have important applications in vaccine development, as a robust innate immunity will likely promote the subsequent adaptive immunity.

DOI: https://doi.org/10.1128/JVI.01939-20
J Cell Mol Med. 2021 Feb 02.

Kinase GSK3β functions as a suppressor in colorectal carcinoma through the FTO-mediated MZF1/c-Myc axis.

Zeyan Zhang, Qianfu Gao, Shanchao Wang.

  Colorectal carcinoma (CRC) poses heavy burden to human health and has an increasing incidence. Currently, the existing biomarkers for CRC bring about restrained clinical benefits. GSK3β is reported to be a novel therapeutic target for this disease but with undefined molecular mechanisms. Thus, we aimed to investigate the regulatory effect of GSK3β on CRC progression via FTO/MZF1/c-Myc axis. Firstly, the expression patterns of GSK3β, FTO, MZF1 and c-Myc were determined after sample collection. Lowly expressed GSK3β but highly expressed FTO, MZF1 and c-Myc were found in CRC. After transfection of different overexpressed and interference plasmids, the underlying mechanisms concerning GSK3β in CRC cell functions were analysed. Additionally, the effect of GSK3β on FTO protein stability was assessed followed by detection of MZF1 m6A modification and MZF1-FTO interaction. Mechanistically, GSK3β mediated ubiquitination of demethylase FTO to reduce FTO expression. Besides, GSK3β inhibited MZF1 expression by mediating FTO-regulated m6A modification of MZF1 and then decreased the proto-oncogene c-Myc expression, thus hampering CRC cell proliferation. We also carried out in vivo experiment to verify the regulatory effect of GSK3β on CRC via FTO-mediated MZF1/c-Myc axis. It was found that GSK3β inhibited CRC growth in vivo which was reversed by overexpressing c-Myc. Taken together, our findings indicate that GSK3β suppresses the progression of CRC through FTO-regulated MZF1/c-Myc axis, shedding light onto a new possible pathway by which GSK3β regulates CRC.

Keywords:  N6-methyladenosine; colorectal carcinoma; fat mass and obesity-associated protein; glycogen synthase kinase 3 beta; myeloid zinc finger 1

DOI:  https://doi.org/10.1111/jcmm.16291
Biochim Biophys Acta Rev Cancer. 2021 Feb 02. pii: S0304-419X(21)00021-4. [Epub ahead of print] 188522

The role of N6-methyladenosine mRNA in the tumor microenvironment.

Min Li, Xuan Zha, Shengjun Wang.

  In recent years, the most widely distributed eukaryotic messenger RNA (mRNA) modification, N6-methyladenosine (m6A), has received a large amount of interest, in part due to the development and advances of high-throughput RNA sequencing. The effects of m6A mRNA on tumor progression have been the most widely studied, and large amounts of conflicting data have been reported due to differences in tumor contexts, cell types or cell states. The majority of these studies were related to the significance of m6A mRNA on tumor cells, including on proliferation, stemness, invasion capability, etc. However, it has been noted that tumorigenesis and tumor progression cannot occur without support from the tumor microenvironment (TME), which contains multiple types of stromal cells, such as infiltrating immune cells (IICs), vascular cells, mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), and various environmental factors. Here, we summarized the contributions of abnormal m6A mRNA in stromal cells within the TME and described the effects of m6A mRNA on TME remodeling.

Keywords:  N6-methyladenosine; Tumor microenvironment; mRNA methylation

DOI:  https://doi.org/10.1016/j.bbcan.2021.188522
Cancers (Basel). 2021 Feb 01. pii: 545. [Epub ahead of print]13(3):

Role of Methylation in Pro- and Anti-Cancer Immunity.

Ali Mehdi, Shafaat A Rabbani.

  DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.

Keywords:  DNA methylation; RNA methylation; S-adenosylmethionine (SAM); T cells; adaptive immunity; cancer; innate immunity; m6A; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers13030545
Front Cell Dev Biol. 2020 ;8 630754

The Complexity of TET2 Functions in Pluripotency and Development.

Vera Garcia-Outeiral, Cristina de la Parte, Miguel Fidalgo, Diana Guallar.

  Ten-eleven translocation-2 (TET2) is a crucial driver of cell fate outcomes in a myriad of biological processes, including embryonic development and tissue homeostasis. TET2 catalyzes the demethylation of 5-methylcytosine on DNA, affecting transcriptional regulation. New exciting research has provided evidence for TET2 catalytic activity in post-transcriptional regulation through RNA hydroxymethylation. Here we review the current understanding of TET2 functions on both DNA and RNA, and the influence of these chemical modifications in normal development and pluripotency contexts, highlighting TET2 versatility in influencing genome regulation and cellular phenotypes.

Keywords:  5hmC; TET2; development; epigenetic; epitranscriptomic; pluripotency; reprogramming

DOI:  https://doi.org/10.3389/fcell.2020.630754