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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Functions of N6-methyladenosine and its role in cancer

Molecular Cancer, Journal Year: 2019, Volume and Issue: 18(1)

Published: Dec. 1, 2019

N6-methyladenosine (m6A) is methylation that occurs in the N6-position of adenosine, which most prevalent internal modification on eukaryotic mRNA. Accumulating evidence suggests m6A modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. M6A installed by methyltransferases, removed demethylases recognized reader proteins, regulate RNA metabolism including translation, splicing, export, degradation microRNA processing. Alteration levels participates cancer pathogenesis development via expression tumor-related genes like BRD4, MYC, SOCS2 EGFR. In this review, we elaborate recent advances research enzymes. We also highlight underlying mechanism progression. Finally, review corresponding potential targets therapy.

Language: Английский

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m6A Modification in Coding and Non-coding RNAs: Roles and Therapeutic Implications in Cancer

Cancer Cell, Journal Year: 2020, Volume and Issue: 37(3), P. 270 - 288

Published: March 1, 2020

Language: Английский

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Role of RNA modifications in cancer

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(6), P. 303 - 322

Published: April 16, 2020

Language: Английский

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The potential role of RNA N6-methyladenosine in Cancer progression

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

Published: May 12, 2020

Abstract N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A installed by methyltransferases (METTL3/14, WTAP, RBM15/15B, VIRMA ZC3H13, termed “writers”), removed demethylases (FTO, ALKBH5, ALKBH3, “erasers”), recognized m6A-binding proteins (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNP, eIF3, “readers”). Accumulating evidence suggests that methylation greatly impacts metabolism involved pathogenesis of many kinds diseases, including cancers. In this review, we focus on physiological functions modification its related regulators, as well potential biological roles these elements human tumors.

Language: Английский

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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

Cancer Cell, Journal Year: 2020, Volume and Issue: 38(1), P. 79 - 96.e11

Published: June 11, 2020

Language: Английский

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m ⁶ A RNA methylation: from mechanisms to therapeutic potential

The EMBO Journal, Journal Year: 2021, Volume and Issue: 40(3)

Published: Jan. 20, 2021

Language: Английский

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ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Proceedings of the National Academy of Sciences, Journal Year: 2020, Volume and Issue: 117(33), P. 20159 - 20170

Published: Aug. 3, 2020

Significance N 6 -methylation of adenosine (m A) RNA modification plays important roles in development and tumorigenesis. The functions mechanisms m A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma colon syngeneic mouse models to study the ALKBH5 FTO anti–PD-1 antibody GVAX vaccination therapy. We found that knockout tumor cells enhances efficacy prolonged survival. modulates target gene expression splicing, leading changes metabolite contents, such as lactate microenvironment, which regulates suppressive lymphocytes Treg myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, observed similar phenotype, indicating future translational application our findings.

Language: Английский

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The role of m6A, m5C and Ψ RNA modifications in cancer: Novel therapeutic opportunities

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

Published: Jan. 18, 2021

Abstract RNA modifications have recently emerged as critical posttranscriptional regulators of gene expression programmes. Significant advances been made in understanding the functional role regulating coding and non-coding processing function, which turn thoroughly shape distinct They affect diverse biological processes, correct deposition many these is required for normal development. Alterations their are implicated several diseases, including cancer. In this Review, we focus on occurrence N 6 -methyladenosine (m A), 5-methylcytosine 5 C) pseudouridine (Ψ) RNAs describe physiopathological We will highlight latest insights into mechanisms how influence tumour development, maintenance, progression. Finally, summarize development small molecule inhibitors that target specific writers or erasers to rewind epitranscriptome a cancer cell therapeutic potential.

Language: Английский

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m ⁶ A RNA methyltransferases METTL3/14 regulate immune responses to anti‐PD‐1 therapy

The EMBO Journal, Journal Year: 2020, Volume and Issue: 39(20)

Published: Sept. 23, 2020

Article23 September 2020Open Access Source Data m6A RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy Lingling Wang Division of Genetics, Department Pediatrics, Program in Immunology, Institute for Genomic Medicine, University California San Diego, La Jolla, CA, USA Search more papers by this author Hui Bioinformatics Program, Kriti Agrawal Yuqi Kang Na Li Rachel Tang orcid.org/0000-0003-0364-6280 Jiajun Yuan Tariq M Rana Corresponding Author [email protected] orcid.org/0000-0001-9558-5766 Diego Center Precision Immunotherapy, Moores Cancer Center, Information Wang1, Hui1,2, Agrawal1,2, Kang1,2, Li1, Tang1, Yuan1 and *,1,3 1Division 2Bioinformatics 3San *Corresponding author. Tel: +1 858 246 1100; E-mail: The EMBO Journal (2020)39:e104514https://doi.org/10.15252/embj.2020104514 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision process including letters, reviewer comments feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract An impressive clinical success has been observed treating variety cancers using immunotherapy with programmed cell death-1 (PD-1) checkpoint blockade. However, limited response most patients treated antibodies remains challenge, requiring better understanding molecular mechanisms limiting immunotherapy. In colorectal cancer (CRC) resistant immunotherapy, mismatch-repair-proficient or microsatellite instability-low (pMMR-MSI-L) tumors have low mutation burden constitute ~85% patients. Here, we show that inhibition N6-methyladenosine (m6A) mRNA modification depletion methyltransferases, Mettl3 Mettl14, enhanced treatment pMMR-MSI-L CRC melanoma. Mettl3- Mettl14-deficient increased cytotoxic tumor-infiltrating CD8+ T cells elevated secretion IFN-γ, Cxcl9, Cxcl10 tumor microenvironment vivo. Mechanistically, Mettl14 loss promoted IFN-γ-Stat1-Irf1 signaling through stabilizing Stat1 Irf1 via Ythdf2. Finally, found negative correlation between METTL3 METTL14 STAT1 59 tumors. Altogether, our findings uncover new awareness function methylation adaptive immunity provide as potential therapeutic targets anticancer Synopsis role maintenance surveillance is unclear. reveal N6-methyadenosine stabilizes transcripts involved Ythdf2, thereby enhancing carcinoma melanoma Disruption sensitizes mice enhances modulates production Cxcl9 Cxcl10. are regulated negatively correlated human tumor. Introduction Immunotherapy become one unprecedented modalities multiple targeting interactions system (Ribas Wolchok, 2018). discriminates exogeneous from self recognition major histocompatibility complex (MHC) complex-peptides presented on target cells, e.g., cell, receptors (TCR) (Schreiber et al, 2011; Khalil 2016), whereas alone not sufficient initiation response. Other regulatory circuits also play important roles co-inhibit co-activate former typically exploited evade immunosurveillance (Townsend Allison, 1993; Sharma 2015; Wei 2018b). Among these pathways, PD-1 (programmed death–1) CTLA-4 (cytotoxic T-lymphocyte protein 4) targeted inhibitors (ICIs) enhance killing (Jenkins Tumors mutated genome likely generate peptide neoantigen recruit activate MHC complex-TCR induce durable (Samstein 2019). Although practice ICIs high burden, such non-small lung (NSCLC) melanoma, while failure elapse low-mutation-burden common (Alexandrov 2013; 2017; Ganesh addition mutational load, number other useful biomarkers ICI identified interferon signatures (Ayers 2017), ligand expression, inflammation microenvironments (Kowanetz Mismatch-repair deficiency level instability (dMMR-MSI-H) emerged an effective biomarker predict solid (Le Mandal dMMR-MSI-H possess (MSI) leading genetic hypermutability accumulation thousands mutations. These studies exciting proof concept reliable could criteria patient stratification therapies. (Ganesh Apart status lack being involves alternations both well their interface (Sharma 2017). Within alternations, abnormality absence antigen presentation, aberrant oncogenic were revealed recent Therefore, governing resistance need be discovered. addition, mechanism-driven should guiding CRC. abundant chemical lncRNA eukaryotes (Dominissini 2012; Meyer Yue Jaffrey, mammalian epitranscriptomic mark installed methyltransferase machinery comprising METTL3-METTL14 core subunits (Liu 2014; Ping 2014). reversal mediated alpha-ketoglutarate-dependent dioxygenases FTO ALKBH5 (Jia Zheng 2013). Dynamics influences broad range physiological processes metabolism translation mainly readout YTH family binding proteins (Wang 2014, Xiao 2016; Hsu Nachtergaele He, Aberrant associated various diseases (Deng 2018; Wu Recently, started emerging its initiation, differentiation, progression (Jaffrey Kharas, Liu Moreover, elevation affects sensitivity within (Han 2019; Yang Despite discovery, suppression had tumorigenesis sensitizing described where gene expression splicing, changes lactate content microenvironment, which regulates composition Treg myeloid-derived suppressor (Li 2020). Remarkably, small-molecule inhibitor efficacy varied suggest much needs done further understand importance dynamic biology application. Besides, apart total whether pathway insensitivity refractory unknown. present disruption modulating intratumor cells. Our uncovered, previously unrecognized, mechanism blockade, providing avenue malignant disease treatment. Results Loss So far, (METTL3 METTL14) investigated. To determine biological process, employed mouse models modestly immunogenic line CT26 (Kim 2014) poorly murine B16 (Manguso generated sgRNA validated effect Western blotting (Fig 1A B). establish models, first investigated checkpoint-blocking antibody We BALB/c bearing control IgG, anti-PD-1, combined plus anti-CTLA-4 antibodies. Anti-PD-1 growth survival compared IgG treatment, responded than EV1A B), consistent previous study showing colon Next, Mettl14-depleted subcutaneously injected into mice, antibody. Compared control, showed slower (Figs 1C EV1C) prolonged 1E). analyzed well-established model C57BL/6J combination granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting irradiated vaccine (GVAX), simulates Consistent results CT26, Mettl14-deficient-B16-tumor-bearing exhibited 1D EV1D) longer controls 1F). Additionally, confirmed efficiently repressed blot EV1E F) Ki-67 was decreased immunohistochemistry (IHC) staining, indicated null smaller caused reduced proliferation EV1G). Then, assessed able affect since lethal particular types leukemia (Barbieri Vu Weng 2018), glioblastoma (Cui hepatocellular (Ma Chen observation all knockout quite similar cellular vitro EV2A) volume vivo EV2B–E). Collectively, suggested generalizable but intrinsically impairs alone. Figure 1. Depletion A, B. Immunoblotting performed validate levels indicated. Gapdh served loading control. C, D. Tumor monitored respectively. mean ± SEM each group. n, numbers mice. *P < 0.05; ***P 0.001 Student's t-tests. E, F. Survival analysis those depleted genes recorded **P 0.01; data available online figure. 1 [embj2020104514-sup-0006-SDataFig1.pdf] Download figure PowerPoint Click here expand EV1. (Related Fig 1) A. measured tumor-bearing (IgG control), P (anti-PD-1 antibody), C (anti-CTLA-4 antibody) modalities. after treatments (C, CT26; D, B16) over time Each represents mouse. Immunoblots carried out triplicates G. Representative images stained IHC analysis. Tissue sections PD1 Scale bars, 50 μm. EV2. no Cell Mettl3, non-targeting (NTC) MTS assay vitro. Mean SD n = 3. B, C. xenografts E. (D, B16). altered identify components tissues flow cytometry. infiltrates contained significantly 2A EV3A), differences CD4+ CD45+ 2A). natural killer (NK) higher observations cytometry analysis, CD8 2B). Further dramatically granzyme B 2C). Consistently, tumors, EV3B C). Taken together, improved investigate contributions antitumor anti-CD8 during completely abolished 2D E), indicating essential controlling 2. cytokine Percentage Treg, NK spot 0.01 staining. B-expressing Mice CD8-depleting PD-1/GVAX points. F, IFN-γ serum (F) (G) ELISA. representatives at least three independent experiments. SEM. 0.05 EV3. Tumor-infiltrating chemokines concentration 2) examples FACS analyses Secretion Intratumoral determined ELISA extracts then calculated concentration. producers (Paliard 1988), predominately secrete cytokines TNFα (Lichterfeld 2004; Pandiyan 2007). plays (Castro 2018) inducing CXCL9 CXCL10, facilitate recruitment effector suppress (Gorbachev 2007; Tokunaga address question, changed 2F EV3F) except EV3D). Interestingly, remarkably 2G), EV3E), EV3G) relative intratumor. Together, indicate microenvironment. Identification sequencing (RNA-seq) affected upon depletion. Through RNA-seq data, transcript 402 upregulated 282 downregulated 283 73 3A). Furthermore, 230 Mettl14-dependent among control: 202 co-upregulated 28 co-downregulated 3B, Dataset EV1). Gene ontology (GO) genes, enriched pathways interferons, defense, inflammation, leukocyte cell–cell adhesion, production, immunity, processing presentation 3C). Notably, interferon-gamma interferon-beta Stat1, Stat4, Irf1, Irf4, Irf7, Pdl1, cytokine/chemokine-mediated Ccl5, Cxcl10, productions EV3E G). results, qRT–PCR interferons cytokine/chemokine EV4A). principally connected response-associated processes. m6A-seq Volcano plot differentially expressed obtained DESeq2 Significantly plotted red blue points, n.s, non-significant. Venn diagrams Meta-enrichment (C). Consensus motifs value HOMER two replicates, Schematic workflow downstream peaks number. sites integrative genomics viewer. representative duplicates results. Red reads coverage IP sample input sample. Rectangular cyan shade located transcripts. enrichment examined RIP-qPCR Mettl3-, Ctla4 functioned SD. p-Stat1 (phosphorylated), triplicate Mettl14-, Mettl3/Stat1-, Mettl3/Irf1-, Mettl14/Stat1-, Mettl14/Irf1-depleted under 3 [embj2020104514-sup-0007-SDataFig3.pdf] EV4. 3) Transcriptional dat

Language: Английский

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