The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: Feb. 28, 2020

Abstract Liver cancer is a common worldwide. Although the etiological factors of liver carcinogenesis are well defined, underlying molecular mechanisms remain largely elusive. Epigenetic deregulations, such as aberrant DNA methylation and histone modifications, play critical role in carcinogenesis. Analogous to core proteins, reversible chemical modifications on mRNA have recently been recognized important regulatory control gene expression. N6-methyladenosine (m6A) most prevalent internal modification mammalian cells. m6A for controlling many cellular biological processes. Deregulation has implicated human carcinogenesis, including cancer. In this review, we summarize recent findings regulation its impacts normal We will focus deregulation regulators diseases cancers. highlight clinical relevance also discuss potential exploiting diagnosis therapeutics.

Language: Английский

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m6A-binding proteins: the emerging crucial performers in epigenetics

Journal of Hematology & Oncology, Journal Year: 2020, Volume and Issue: 13(1)

Published: April 10, 2020

Abstract N 6 -methyladenosine (m A) is a well-known post-transcriptional modification that the most common type of methylation in eukaryotic mRNAs. The regulation m A dynamic and reversible, which erected by methyltransferases (“writers”) removed demethylases (“erasers”). Notably, effects on targeted mRNAs resulted predominantly depend functions different A-binding proteins (“readers”) including YT521-B homology (YTH) domain family, heterogeneous nuclear ribonucleoproteins (HNRNPs), insulin-like growth factor 2 mRNA-binding (IGF2BPs). Indeed, readers not only participate multiple procedures RNA metabolism, but also are involved variety biological processes. In this review, we summarized specific underlying mechanisms tumorigenesis, hematopoiesis, virus replication, immune response, adipogenesis.

Language: Английский

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Interaction between N6-methyladenosine (m6A) modification and noncoding RNAs in cancer

Molecular Cancer, Journal Year: 2020, Volume and Issue: 19(1)

Published: May 22, 2020

As a critical internal RNA modification in higher eukaryotes, N6-methyladenosine (m6A) has become the hotspot of epigenetics research recent years. Extensive studies on messenger RNAs have revealed that m6A affects fate and cell functions various bioprocesses, such as splicing, export, translation, stability, some which seem to be directly or indirectly regulated by noncoding RNAs. Intriguingly, abundant microRNAs, long RNAs, circular small nuclear ribosomal are also highly modified with require for their biogenesis functions. Here, we discuss interaction between focusing functional relevance cancer progression, metastasis, drug resistance, immune response. Furthermore, investigation regulatory proteins its inhibitors provides new opportunities early diagnosis effective treatment cancer, especially combination immunotherapy.

Language: Английский

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The N⁶-methyladenosine (m⁶A)-forming enzyme METTL3 facilitates M1 macrophage polarization through the methylation of STAT1 mRNA

AJP Cell Physiology, Journal Year: 2019, Volume and Issue: 317(4), P. C762 - C775

Published: July 31, 2019

Compelling evidence indicates that epigenetic regulations orchestrate dynamic macrophage polarization. N6-methyladenosine (m6A) methylation is the most abundant modification of mammalian mRNA, but its role in polarization still completely unknown. Here, we show m6A-catalytic enzyme methyltransferase like 3 (METTL3) specifically upregulated following M1 mouse macrophages. Furthermore, METTL3 knockdown through siRNA transfection markedly inhibited M1, enhanced M2, Conversely, overexpression via plasmid greatly facilitated attenuated Further methylated RNA immunoprecipitation and vitro m6A assays suggested directly methylates mRNA encoding signal transducer activator transcription 1 (STAT1), a master factor controlling polarization, at coding sequence 3'-untranslated regions. In addition, METTL3-mediated STAT1 significantly increased stability subsequently expression. conclusion, drives by methylating potentially serving as an anti-inflammatory target.

Language: Английский

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RNA modifications: importance in immune cell biology and related diseases

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: Sept. 22, 2022

RNA modifications have become hot topics recently. By influencing processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune abnormality in human diseases is also a research focus progressing rapidly these years. Studies demonstrated that participate the multiple biological processes cells, development, differentiation, activation, migration, polarization, thereby modulating responses are involved some related diseases. In this review, we present existing knowledge functions underlying mechanisms modifications, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, summarize their roles Via regulating can pathogenesis diseases, such cancers, infection, inflammatory autoimmune We further highlight challenges future directions based on knowledge. All all, review will provide helpful well novel ideas for researchers area.

Language: Английский

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Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(640)

Published: April 13, 2022

The role of N6-methyladenosine (m6A) modifications in renal diseases is largely unknown. Here, we characterized the N6-adenosine-methyltransferase-like 3 (METTL3), whose expression elevated tubules different acute kidney injury (AKI) models as well human biopsies and cultured tubular epithelial cells (TECs). METTL3 silencing alleviated inflammation programmed cell death TECs response to stimulation by tumor necrosis factor-α (TNF-α), cisplatin, lipopolysaccharide (LPS), whereas overexpression had opposite effects. Conditional knockout from mouse kidneys attenuated cisplatin- ischemic/reperfusion (I/R)-induced dysfunction, injury, inflammation. Moreover, TAB3 [TGF-β-activated kinase 1 (MAP3K7) binding protein 3] was identified a target m6A methylated RNA immunoprecipitation sequencing sequencing. stability increased through IGF2BP2 (insulin-like growth factor 2 2) its m6A-modified stop codon regions. proinflammatory effects were then explored both vitro vivo. Adeno-associated virus 9 (AAV9)-mediated LPS-induced AKI models. We further Cpd-564 inhibitor that better protective against ischemia/reperfusion-induced than S-adenosyl-l-homocysteine, previously inhibitor. Collectively, promoted enhanced via IGF2BP2-dependent mechanisms. Both genetic pharmacological inhibition inflammation, suggesting METTL3/TAB3 axis potential for treatment AKI.

Language: Английский

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Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer

Molecular Cancer, Journal Year: 2021, Volume and Issue: 20(1)

Published: Feb. 8, 2021

The four major RNA adenosine modifications, i.e., m

Language: Английский

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The plasticity of mRNA translation during cancer progression and therapy resistance

Nature reviews. Cancer, Journal Year: 2021, Volume and Issue: 21(9), P. 558 - 577

Published: Aug. 2, 2021

Language: Английский

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The roles and implications of RNA m6A modification in cancer

Nature Reviews Clinical Oncology, Journal Year: 2023, Volume and Issue: 20(8), P. 507 - 526

Published: May 23, 2023

Language: Английский

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m⁶A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Theranostics, Journal Year: 2020, Volume and Issue: 11(5), P. 2201 - 2217

Published: Dec. 16, 2020

Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also potential roles immune regulation tumor microenvironment (TME) formation. Methods: In this study, we curated 23 regulators performed consensus molecular subtyping with NMF algorithm to determine patterns m6A-related gene signature colon cancer (CC). The ssGSEA CIBERSORT algorithms were employed quantify relative infiltration levels various cell subsets. An PCA based m6Sig scoring scheme was used evaluate individual tumors an response. Results: Three distinct identified among 1307 CC samples, which associated different clinical outcomes pathways. TME characterization revealed that highly consistent three known profiles: immune-inflamed, immune-excluded, immune-desert, respectively. Based on score, extracted from genes, patients can be divided into high low score subgroups. Patients lower characterized by prolonged survival time enhanced infiltration. Further analysis indicated correlated greater mutation loads, PD-L1 expression, higher rates SMGs (e.g., PIK3CA SMAD4). addition, scores showed a better responses durable benefits independent immunotherapy cohorts. Conclusions: This study highlights is significantly diversity complexity. Quantitatively evaluating will strengthen our understanding characteristics promote more effective strategies.

Language: Английский

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