The role of m6A modification in the biological functions and diseases

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: Feb. 21, 2021

Abstract N 6 -methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher cells. m6A modified by methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, KIAA1429, and, removed demethylases, erasers, including FTO ALKBH5. It recognized m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 HNRNPA2B1, also known “readers”. Recent studies have shown that RNA plays essential role both physiological pathological conditions, initiation progression of different types human cancers. In this review, we discuss how methylation influences progressions hematopoietic, central nervous reproductive systems. We will mainly focus on recent progress identifying biological functions underlying molecular mechanisms methylation, its regulators downstream target genes, during cancer above propose process offer potential targets for therapy future.

Language: Английский

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m6A-dependent glycolysis enhances colorectal cancer progression

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

Published: April 3, 2020

Abstract Background Epigenetic alterations are involved in various aspects of colorectal carcinogenesis. N 6 -methyladenosine (m A) modifications RNAs emerging as a new layer epigenetic regulation. As the most abundant chemical modification eukaryotic mRNA, m A is essential for regulation mRNA stability, splicing, and translation. Alterations regulatory genes play important roles pathogenesis variety human diseases. However, whether this participates glucose metabolism cancer (CRC) remains uncharacterized. Methods Transcriptome-sequencing liquid chromatography-tandem mass spectrometry (LC-MS) were performed to evaluate correlation between CRC. Mass spectrometric metabolomics analysis, vitro vivo experiments conducted investigate effects METTL3 on CRC glycolysis tumorigenesis. RNA MeRIP-sequencing, immunoprecipitation stability assay used explore molecular mechanism Results strong 18 F-FDG uptake was observed patients from Xuzhou Central Hospital. induced-CRC tumorigenesis depends cell multiple models. Mechanistically, directly interacted with 5′/3’UTR regions HK2 , 3’UTR region SLC2A1 (GLUT1), then further stabilized these two activated pathway. M A-mediated (GLUT1) stabilization relied reader IGF2BP2 or IGF2BP2/3, respectively. Conclusions functional clinical oncogene stabilizes expression through an A-IGF2BP2/3- dependent mechanism. Targeting its pathway offer alternative rational therapeutic targets high metabolism.

Language: Английский

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METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer

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

Published: June 17, 2020

Colorectal cancer (CRC) is one of the leading causes tumor-related death worldwide, and its main cause distant metastasis. Methyltransferase-like 14(METTL14), a major RNA N6-adenosine methyltransferase, involved in tumor progression via regulating function. The goal study to uncover biological function molecular mechanism METTL14 CRC.Quantitative real-time PCR (qRT-PCR), western blot immunohistochemical (IHC) assays were employed detect SOX4 CRC cell lines tissues. functions demonstrated using vitro vivo experiments. Chromatin immunoprecipitation (ChIP), Transcrptomic sequencing (RNA-Seq), m6A-RNA (MeRIP-Seq), luciferase reporter used explore action.METTL14 expression was significantly downregulated decreased associated with poor overall survival (OS). Both univariate multivariate Cox regression analysis indicated that an independent prognostic factor CRC. Moreover, lysine-specific histone demethylase 5C(KDM5C)-mediated demethylation H3 lysine 4 tri-methylation(H3K4me3) promoter inhibited transcription. Functionally, we verified cells migration, invasion metastasis through assays, respectively. Furthermore, identified SRY-related high-mobility-group box 4(SOX4) as target METTL14-mediated m6A modification. Knockdown markedly abolished mRNA modification elevated expression. We also revealed degradation relied on YTHDF2-dependent pathway. Lastly, might inhibit malignant process partly SOX4-mediated EMT PI3K/Akt signals.Decreased facilitates CRC, suggesting be potential biomarker effective therapeutic for

Language: Английский

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METTL3-mediated m ⁶ A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression

Annals of the Rheumatic Diseases, Journal Year: 2021, Volume and Issue: 81(1), P. 85 - 97

Published: Oct. 27, 2021

Objective The aim of the study was to investigate role and regulatory mechanisms fibroblast-like synoviocytes (FLSs) their senescence in progression osteoarthritis (OA). Methods Synovial tissues from normal patients with OA were collected. Synovium FLS analysed by immunofluorescence western blotting. methyltransferase-like 3 (METTL3) autophagy regulation explored using N6-methyladenosine (m 6 A)-methylated RNA immunoprecipitation assays. Mice subjected destabilisation medial meniscus (DMM) surgery intra-articularly injected or without pAAV9 loaded small interfering (siRNA) targeting METTL3. Histological analysis performed determine cartilage damage. Results Senescent FLSs markedly increased mouse models. We determined that impaired occurred OA-FLS, resulting upregulation senescence-associated secretory phenotype (SASP). Re-establishment reversed senescent suppressing GATA4. Further, we observed for first time excessive m A modification negatively regulated OA-FLS. Mechanistically, METTL3-mediated decreased expression autophagy-related 7, an E-1 enzyme crucial formation autophagosomes, attenuating its stability. Silencing METTL3 enhanced autophagic flux inhibited SASP Intra-articular injection synovium-targeted siRNA suppressed cellular propagation joints ameliorated DMM-induced destruction. Conclusions Our revealed important progression. Targeted inhibition could alleviate limit development experimental animal models, providing a potential strategy therapy.

Language: Английский

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Biomolecular Condensates and Cancer

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(2), P. 174 - 192

Published: Jan. 9, 2021

Language: Английский

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Fusobacterium nucleatum, a key pathogenic factor and microbial biomarker for colorectal cancer

Trends in Microbiology, Journal Year: 2022, Volume and Issue: 31(2), P. 159 - 172

Published: Sept. 1, 2022

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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Insights into N6-methyladenosine and programmed cell death in cancer

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Jan. 28, 2022

Abstract N6-methyladenosine (m6A) methylation, the most common form of internal RNA modification in eukaryotes, has gained increasing attention and become a hot research topic recent years. M6A plays multifunctional roles normal abnormal biological processes, its role may vary greatly depending on position m6A motif. Programmed cell death (PCD) includes apoptosis, autophagy, pyroptosis, necroptosis ferroptosis, which involve breakdown plasma membrane. Based implications methylation PCD, regulators functional were comprehensively studied reported. In this review, we focus high-complexity links between different types PCD pathways, are then closely associated with initiation, progression resistance cancer. Herein, clarifying relationship is great significance to provide novel strategies for cancer treatment, potential prospect clinical application.

Language: Английский

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N6-Methyladenosine–Mediated Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells’ Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways

Gastroenterology, Journal Year: 2023, Volume and Issue: 164(6), P. 990 - 1005

Published: Feb. 8, 2023

Background & Aims

Hepatocellular carcinoma (HCC) is one of the leading causes cancer-related deaths worldwide, but there a deficiency early diagnosis biomarkers and therapeutic targets. Drug resistance accounts for most HCC-related deaths, yet mechanisms underlying drug remain poorly understood.

Methods

Expression Frizzled-10 (FZD10) in liver cancer stem cells (CSCs) was identified by means RNA sequencing validated real-time polymerase chain reaction immunohistochemistry. In vitro vivo experiments were used to assess effect FZD10 on CSC expansion lenvatinib resistance. sequencing, binding protein immunoprecipitation, luciferase report assays applied explore mechanism FZD10-mediated CSCs

Results

Activation mediated METTL3-dependent N6-methyladenosine methylation messenger RNA. Functional studies revealed that promotes self-renewal, tumorigenicity, metastasis via activating β-catenin YAP1. The FZD10–β-catenin/YAP1 axis activated predicts poor prognosis. Moreover, FZD10–β-catenin/c-Jun transcriptionally activates METTL3 expression, forming positive feedback loop. Importantly, FZD10/β-catenin/c-Jun/MEK/ERK determines responses hepatoma treatment. Analysis patient cohort, patient-derived tumor organoids, xenografts further suggest might predict clinical benefit patients with HCC. Furthermore, treatment lenvatinib-resistant HCC adeno-associated virus targeting or inhibitor restored response.

Conclusions

Elevated expression resistance, indicating novel prognostic biomarker target human

Language: Английский

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IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression

Theranostics, Journal Year: 2020, Volume and Issue: 11(3), P. 1100 - 1114

Published: Dec. 16, 2020

N6-methyladenosine (m

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