Roles of METTL3 in cancer: mechanisms and therapeutic targeting

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

Published: Aug. 27, 2020

N6-methyladenosine (m6A) is the most abundant mRNA modification and catalyzed by methyltransferase complex, in which methyltransferase-like 3 (METTL3) sole catalytic subunit. Accumulating evidence recent years reveals that METTL3 plays key roles a variety of cancer types, either dependent or independent on its m6A RNA activity. While modifications have been extensively reviewed elsewhere, critical functions various types cancer, as well potential targeting treatment, not yet highlighted. Here we summarize our current understanding both oncogenic tumor-suppressive METTL3, underlying molecular mechanisms. The well-documented protein structure METTL3/METTL14 heterodimer provides basis for therapeutic targeting, also discussed this review.

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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m6A modification: recent advances, anticancer targeted drug discovery and beyond

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

Published: Feb. 14, 2022

Abstract Abnormal N6-methyladenosine (m6A) modification is closely associated with the occurrence, development, progression and prognosis of cancer, aberrant m6A regulators have been identified as novel anticancer drug targets. Both traditional medicine-related approaches modern discovery platforms used in an attempt to develop m6A-targeted drugs. Here, we provide update latest findings on critical roles cancer progression, summarize rational sources for agents from medicines computer-based chemosynthetic compounds. This review highlights potential targeting treatment proposes advantage artificial intelligence (AI) m6A-targeting Graphical abstract Three stages discovery: medicine-based natural products, chemical or synthesis, (AI)-assisted future.

Language: Английский

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Mechanism of RNA modification N6-methyladenosine in human cancer

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

Published: June 8, 2020

Abstract Since the breakthrough discoveries of DNA and histone modifications, field RNA modifications has gained increasing interest in scientific community. The discovery N6-methyladenosine (m6A), a predominantly internal epigenetic modification eukaryotes mRNA, heralded creation epi-transcriptomics. This post-transcriptional is dynamic reversible, regulated by methylases, demethylases proteins that preferentially recognize m6A modifications. Altered levels affect processing, degradation translation, thereby disrupting gene expression key cellular processes, ultimately resulting tumor initiation progression. Furthermore, inhibitors regulators m6A-related factors have been explored as therapeutic approaches for treating cancer. In present review, mechanisms modification, clinicopathological relevance alterations, type frequency alterations multiple functions it regulates different types cancer are discussed.

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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Novel insights into the interplay between m6A modification and noncoding RNAs in cancer

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

Published: Aug. 7, 2020

N6-methyladenosine (m6A) is one of the most common RNA modifications in eukaryotes, mainly messenger (mRNA). Increasing evidence shows that m6A methylation modification acts an essential role various physiological and pathological bioprocesses. Noncoding RNAs (ncRNAs), including miRNAs, lncRNAs circRNAs, are known to participate regulating cell differentiation, angiogenesis, immune response, inflammatory response carcinogenesis. regulators, such as METTL3, ALKBH5 IGF2BP1 have been reported execute a m6A-dependent ncRNAs involved Meanwhile, can target or modulate regulators influence cancer development. In this review, we provide insight into interplay between cancer.

Language: Английский

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Role of main RNA modifications in cancer: N6-methyladenosine, 5-methylcytosine, and pseudouridine

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

Published: April 28, 2022

Cancer is one of the major diseases threatening human life and health worldwide. Epigenetic modification refers to heritable changes in genetic material without any nucleic acid sequence results phenotypic changes. modifications regulate many biological processes, such as growth, aging, various diseases, including cancer. With advancement next-generation sequencing technology, role RNA cancer progression has become increasingly prominent a hot spot scientific research. This review studied several common modifications, N6-methyladenosine, 5-methylcytosine, pseudouridine. The deposition roles these coding noncoding RNAs are summarized detail. Based on background, this expression, function, underlying molecular mechanism their regulators further discussed some existing small-molecule inhibitors. More in-depth studies needed broaden understanding epigenetics diagnosis, treatment, prognosis.

Language: Английский

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RNA Modifications and Epigenetics in Modulation of Lung Cancer and Pulmonary Diseases

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(19), P. 10592 - 10592

Published: Sept. 30, 2021

Lung cancer is the leading cause of cancer-related mortality worldwide, and its tumorigenesis involves accumulation genetic epigenetic events in respiratory epithelium. Epigenetic modifications, such as DNA methylation, RNA modification, histone have been widely reported to play an important role lung development other pulmonary diseases. Whereas functionality chromatin modifications referred epigenetics characterized, various nucleotides recently come into prominence functionally important. N6-methyladosine (m6A) most prevalent internal modification mRNAs, machinery writers, erasers, readers well-characterized. However, several nucleotide mRNAs noncoding RNAs also shown regulation biological processes pathology. Such epitranscriptomic regulating aspects metabolism, including transcription, translation, splicing, stability. The dysregulation has implicated pathological associated with carcinogenesis uncontrolled cell proliferation, migration, invasion, epithelial-mesenchymal transition. In recent years, advancement sequencing technology, high-resolution maps different tissues, organs, or disease models are being constantly at a dramatic speed. This facilitates further understanding relationship between epitranscriptomics, shedding light on new therapeutic possibilities. this review, we summarize basic information m6A, m1A, m5C, m7G, pseudouridine, A-to-I editing. We then demonstrate their relation kinds diseases, especially cancer. By comparing roles review may provide some insights offer better involvement

Language: Английский

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METTL3 promotes intrahepatic cholangiocarcinoma progression by regulating IFIT2 expression in an m6A-YTHDF2-dependent manner

Oncogene, Journal Year: 2022, Volume and Issue: 41(11), P. 1622 - 1633

Published: Jan. 29, 2022

Abstract N6-methyladenosine (m 6 A) RNA methylation has recently been found involving in regulatory mechanism of the tumor progression. Our aim was to explore biological function and clinical significance m A methyltransferase METTL3 intrahepatic cholangiocarcinoma (ICC). In this study, we revealed that upregulated predicted poor prognosis patients with ICC. Multivariate regression analysis demonstrated expression an independent predictor for overall survival Moreover, knockdown inhibited ICC progression, while overexpression showed opposite effect. inhibitor STM2457 also anti-tumor effect Mechanistically, transcription driven by H3K4me3 activation. Upregulation mediated modification IFIT2 mRNA accelerated decay a YTHDF2-dependent manner, which promoted development lead poorer prognosis. summary, our findings activation-driven METTL 3 promotes progression YTHDF2-mediated degradation, suggesting may serve as potential target human therapy.

Language: Английский

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Small RNA modifications: regulatory molecules and potential applications

Journal of Hematology & Oncology, Journal Year: 2023, Volume and Issue: 16(1)

Published: June 22, 2023

Abstract Small RNAs (also referred to as small noncoding RNAs, sncRNA) are defined polymeric ribonucleic acid molecules that less than 200 nucleotides in length and serve a variety of essential functions within cells. RNA species include microRNA (miRNA), PIWI-interacting (piRNA), interfering (siRNA), tRNA-derived (tsRNA), etc. Current evidence suggest can also have diverse modifications their nucleotide composition affect stability well capacity for nuclear export, these relevant drive molecular signaling processes biogenesis, cell proliferation differentiation. In this review, we highlight the characteristics cellular modifications, current techniques reliable detection. We discuss how may be clinical applications diagnosis treatment human health conditions such cancer.

Language: Английский

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