N6-methyladenosine reader YTHDF family in biological processes: Structures, roles, and mechanisms

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Март 14, 2023

As the most abundant and conserved internal modification in eukaryote RNAs, N6-methyladenosine (m 6 A) is involved a wide range of physiological pathological processes. The YT521-B homology (YTH) domain-containing family proteins (YTHDFs), including YTHDF1, YTHDF2, YTHDF3, are class cytoplasmic m A-binding defined by vertebrate YTH domain, exert extensive functions regulating RNA destiny. Distinct expression patterns YTHDF specific cell types or developmental stages result prominent differences multiple biological processes, such as embryonic development, stem fate, fat metabolism, neuromodulation, cardiovascular effect, infection, immunity, tumorigenesis. mediates tumor proliferation, metastasis, drug resistance, possesses potential predictive therapeutic biomarkers. Here, we mainly summary structures, roles, mechanisms especially cancers, well their current limitations future considerations. This will provide novel angles for deciphering A regulation system.

Язык: Английский

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Oncometabolite D-2HG drives tumor metastasis and protumoral macrophage polarization by targeting FTO/m6A/ANGPTL4/integrin axis in triple-negative breast cancer

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Фев. 6, 2025

Abstract Background D-2-hydroxyglutarate (D-2HG), an oncometabolite derived from the tricarboxylic acid cycle. Previous studies have reported diverse effects of D-2HG in pathophysiological processes, yet its role breast cancer remains largely unexplored. Methods We applied advanced biosensor approach to detect levels samples. then investigated biological functions through multiple vitro and vivo assays. A joint MeRIP-seq RNA-seq strategy was used identify target genes regulated by D-2HG-mediated N6-methyladenosine (m 6 A) modification. RNA pull-down assays were further reader that could specifically recognize m modification on angiopoietin like 4 (ANGPTL4) mRNA immunoprecipitation confirm findings. Results found accumulated triple-negative (TNBC), exerting oncogenic both promoting TNBC cell growth metastasis. Mechanistically, enhanced global modifications cells, notably upregulating ANGPTL4 mRNA, which mediated inhibition Fat-mass obesity-associated protein (FTO), resulting increased recognition A-modified YTH binding F1 (YTHDF1), thereby translation ANGPTL4. As a secretory protein, subsequently activated integrin-mediated JAK2/STAT3 signaling cascade cells autocrine signaling. Notably, knockdown or treatment with GLPG1087 (an integrin antagonist) significantly reduced D-2HG-induced proliferation metastasis cells. Additionally, promote macrophage M2 polarization within tumor microenvironment via paracrine signaling, driving progression. The association poor prognosis patients underscores clinical relevance. Conclusions Our study unveils previously unrecognized for progression targeting D-2HG/FTO/m A/ANGPTL4/integrin axis can serve as promising therapeutic patients.

Язык: Английский

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Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Journal of Hematology & Oncology, Год журнала: 2022, Номер 15(1)

Опубликована: Июль 6, 2022

Abstract The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, immunosuppression. One the most common RNA N6-methyladenosine (m 6 A) methylation, widely involved regulation physiological pathological processes, including development. Compelling evidence indicates that m A methylation regulates transcription protein expression through shearing, export, translation, processing, thereby participating dynamic evolution TME. Specifically, methylation-mediated adaptation to phenotypic shift immune cells synergistically promote formation an immunosuppressive supports proliferation metastasis. In this review, we have focused on involvement tumor-adaptive described detailed linking change cell biological functions. view collective data, advocate treating as complete ecosystem components crosstalk with each other achieve adaptive changes. Finally, describe potential utility methylation-targeted therapies immunotherapy clinical applications challenges faced, aim advancing research.

Язык: Английский

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The epigenetic regulatory mechanism of PIWI/piRNAs in human cancers

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Март 7, 2023

Abstract PIWI proteins have a strong correlation with PIWI-interacting RNAs (piRNAs), which are significant in development and reproduction of organisms. Recently, emerging evidences indicated that apart from the reproductive function, PIWI/piRNAs abnormal expression, also involve greatly varieties human cancers. Moreover, usually expressed only germ cells hardly somatic cells, so expression different types cancer offer promising opportunity for precision medicine. In this review, we discussed current researches about biogenesis piRNA, its epigenetic regulatory mechanisms cancers, such as N6-methyladenosine (m 6 A) methylation, histone modifications, DNA methylation RNA interference, providing novel insights into markers clinical diagnosis, treatment prognosis

Язык: Английский

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METTL14-dependent maturation of pri-miR-17 regulates mitochondrial homeostasis and induces chemoresistance in colorectal cancer

Cell Death and Disease, Год журнала: 2023, Номер 14(2)

Опубликована: Фев. 21, 2023

Abstract miR-17-5p has been found to be involved in the proliferation and metastasis of colorectal cancer (CRC), N 6 -methyladenosine (m A) modification is most common RNA eukaryotes. However, whether contributes chemotherapy sensitivity CRC via m A unclear. In this study, we that overexpression led less apoptosis lower drug vitro vivo under 5-fluorouracil (5-FU) treatment, which indicated 5-FU resistance. Bioinformatic analysis suggested miR-17-5p-mediated chemoresistance was associated with mitochondrial homeostasis. directly bound 3’ untranslated region Mitofusin 2 ( MFN2 ), leading decreased fusion enhanced fission mitophagy. Meanwhile, methyltransferase-like protein 14 (METTL14) downregulated CRC, resulting level. Moreover, low level METTL14 promoted expression pri-miR-17 miR-17-5p. Further experiments mRNA methylation initiated by inhibits decay reducing recognition YTHDC2 “GGACC” binding site. The METTL14/miR-17-5p/MFN2 signaling axis may play a critical role CRC.

Язык: Английский

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Delivery of Engineered Primary Tumor-Derived Exosomes Effectively Suppressed the Colorectal Cancer Chemoresistance and Liver Metastasis

ACS Nano, Год журнала: 2023, Номер 17(11), С. 10313 - 10326

Опубликована: Май 4, 2023

Liver metastasis is one of the major causes colorectal cancer (CRC)-related morbidity and mortality. Delivering small interfering RNAs (siRNAs) or noncoding has been reported as a promising method to target liver chemoresistance in CRC. Here, we report RNA delivery system using exosomes derived from primary patient cells. Coiled-coil domain-containing protein 80 (CCDC80) was strongly associated with CRC chemoresistance, finding validated by bioinformatic analysis clinical specimens. Silencing CCDC80 significantly increased sensitivity chemotherapy agents OXA-resistant cell lines mouse model. The cell-derived exosome designed simultaneously deliver siRNAs targeting increase distant models patient-derived xenograft models. We further antitumor effect an ex vivo model chemoresistant organoids organoid Tumor-bearing mice treated siRNA-delivering hepatectomy showed ideal overall survival. Our results provide therapeutic represent possible alternative for patients cases chemoresistance.

Язык: Английский

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Modulation of miR-146b by N6-methyladenosine modification remodels tumor-associated macrophages and enhances anti-PD-1 therapy in colorectal cancer

Cellular Oncology, Год журнала: 2023, Номер 46(6), С. 1731 - 1746

Опубликована: Июль 5, 2023

Abstract Purpose MicroRNA-146b (miR-146b) alleviates experimental colitis in mice by mediating macrophage polarization and the release of inflammatory factors. Our goals were to evaluate antitumor efficacy miR-146b colorectal cancer (CRC) investigate underlying mechanisms. Methods We used murine models CRC whether influenced progression tumors independent tumor-associated macrophages (TAMs). RNA immunoprecipitation, N 6-methyladenosine (m 6 A) immunoprecipitation vitro pri-miRNA processing assays conducted examine m A mediates maturation pri-miR-146b/miR-146b. In a series vivo experiments, we further defined molecular mechanisms methyltransferase-like 3 (METTL3)/miR-146b-mediated immunity its combination with anti-PD-1 immunotherapy. Results found that deletion supported tumor increasing number alternatively activated (M2) TAMs. Mechanistically, A-related “writer” protein METTL3 “reader” HNRNPA2B1 controlled regulating modification region pri-miR-146b. Furthermore, promoted M2-TAMs enhancing phosphoinositide 3-kinase (PI3K)/AKT signaling, this effect was mediated class IA PI3K catalytic subunit p110β, which reduced T cell infiltration, aggravated immunosuppression ultimately progression. knockdown or induced programmed death ligand 1 (PD-L1) production via p110β/PI3K/AKT pathway TAMs consequently augmented activity Conclusions The pri-miR-146b is A-dependent, deletion-mediated TAM differentiation promotes development activating PI3K/AKT pathway, induces upregulation PD-L1 expression, inhibits infiltration into TME enhances findings reveal targeting can serve as an adjuvant Graphical

Язык: Английский

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m6A modification in inflammatory bowel disease provides new insights into clinical applications

Biomedicine & Pharmacotherapy, Год журнала: 2023, Номер 159, С. 114298 - 114298

Опубликована: Янв. 25, 2023

Inflammatory bowel disease (IBD) results from a complex interplay between genetic predisposition, environmental factors, and gut microbes. The role of N6-methyladenosine (m6A) methylation in the pathogenesis IBD has attracted increasing attention. m6A modification not only regulates intestinal mucosal immunity barrier function, but also affects apoptosis autophagy epithelial cells. Additionally, participated interaction microbes host, providing novel direction to explore molecular mechanisms theoretical basis for specific microorganism-oriented prevention treatment measures. regulators are expected be biomarkers predicting prognosis patients. may utilized as target management IBD. This review focused on recent advances how causes initiation development IBD, provided new insights into optimal measures

Язык: Английский

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Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Март 9, 2024

Abstract Despite advancements in treatment protocols, cancer is one of the leading cause deaths worldwide. Therefore, there a need to identify newer and personalized therapeutic targets along with screening technologies combat cancer. With advent pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, lipidomics, scientific community has witnessed an improved molecular metabolomic understanding various diseases, including In addition, three-dimensional (3-D) disease models have been efficiently utilized for pathophysiology tools drug discovery. An integrated approach utilizing 3-D vitro tumor led intricate network encompassing signalling pathways cross-talk solid tumors. present review, we underscore current trends omics highlight their role genotypic-phenotypic co-relation respect models. We further discuss challenges associated provide our outlook on future applications these discovery precision medicine management Graphical

Язык: Английский

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METTL16 suppressed the proliferation and cisplatin-chemoresistance of bladder cancer by degrading PMEPA1 mRNA in a m6A manner through autophagy pathway

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(4), С. 1471 - 1491

Опубликована: Янв. 1, 2024

N6-methyladenosine (m6A) is important in the physiological processes of many species.Methyltransferase-like 16 (METTL16) a novel discovered m6A methylase, regulating various tumors an m6A-dependent manner.However, its function bladder cancer (BLCA) remains largely unclear.In present study, we found that low expression METTL16 predicted poor survival BLCA patients.METTL16 inhibited proliferation and cisplatin-resistance cells vitro vivo.In addition, reduced mRNA stability prostate transmembrane protein androgen induced-1 (PMEPA1) via binding to site 3'-UTR, thereby increased sensitivity cisplatin through PMEPA1-mediated autophagy pathway.Finally, hypoxia-inducible factor 2α (HIF-2α) exerted tumor-promoting effect by promoter region repress transcription.Taken together, High better BLCA.METTL16 significantly cell sensitized HIF-2α-METTL16-PMEPA1-autophagy axis manner.These findings might provide fresh insights into therapy.

Язык: Английский

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