The role, mechanism, and application of RNA methyltransferase METTL14 in gastrointestinal cancer

Molecular Cancer, Год журнала: 2022, Номер 21(1)

Опубликована: Авг. 16, 2022

Abstract Gastrointestinal cancer is the most common human malignancy characterized by high lethality and poor prognosis. Emerging evidences indicate that N6-methyladenosine (m6A), abundant post-transcriptional modification in eukaryotes, exerts important roles regulating mRNA metabolism including stability, decay, splicing, transport, translation. As key component of m6A methyltransferase complex, methyltransferase-like 14 (METTL14) catalyzes methylation on or non-coding RNA to regulate gene expression cell phenotypes. Dysregulation METTL14 was deemed be involved various aspects gastrointestinal cancer, such as tumorigenesis, progression, chemoresistance, metastasis. Plenty findings have opened up new avenues for exploring therapeutic potential targeting METTL14. In this review, we systematically summarize recent advances regarding biological functions discuss its clinical applications propose research forecast.

Язык: Английский

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ALKBH5 attenuates mitochondrial fission and ameliorates liver fibrosis by reducing Drp1 methylation

Pharmacological Research, Год журнала: 2022, Номер 187, С. 106608 - 106608

Опубликована: Дек. 21, 2022

Mitochondrial metabolism plays a pivotal role in various cellular processes and fibrosis. However, the mechanism underlying mitochondrial metabolic function liver fibrosis remains poorly understood. In this study, we determined whether mediates using cells, animal models, clinical samples to elucidate potential effects of We report that AlkB Homolog 5 (ALKBH5) decreases membrane (MMP) oxygen consumption rate (OCR), suppresses fission hepatic stellate cell (HSC) proliferation migration ameliorates Enhancement fission, an essential event during HSC migration, is dependent on decreased ALKBH5 expression. Furthermore, reveal low expression associated with elevated N6-methyladenosine (m6A) mRNA levels. Mechanistically, m6A demethylation 3’UTR Drp1 induces its translation YTH domain family proteins 1 (YTHDF1)-independent manner. Subsequently, transforming growth factor-β1 (TGF-β1) induced HSC, Dynamin-related protein (Drp1) increases migration. Decreased inhibits Notably, human fibrotic heart tissue exhibited enhanced fission; increased YTHDF1, Drp1, alpha-smooth muscle actin (α-SMA) collagen I expression; Our results highlight novel by which reducing methylation m6A-YTHDF1-dependent manner, may indicate demethylation-based approach for diagnosis therapy.

Язык: Английский

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Epigenetic modification in liver fibrosis: Promising therapeutic direction with significant challenges ahead

Acta Pharmaceutica Sinica B, Год журнала: 2023, Номер 14(3), С. 1009 - 1029

Опубликована: Ноя. 4, 2023

Liver fibrosis, characterized by scar tissue formation, can ultimately result in liver failure. It's a major cause of morbidity and mortality globally, often associated with chronic diseases like hepatitis or alcoholic non-alcoholic fatty diseases. However, current treatment options are limited, highlighting the urgent need for development new therapies. As reversible regulatory mechanism, epigenetic modification is implicated many biological processes, including fibrosis. Exploring mechanisms involved fibrosis could provide valuable insights into developing treatments diseases, although evidence still controversial. This review provides comprehensive summary critical targets modifications, DNA methylation, histone modification, RNA fibrotic The potential cooperation different modifications promoting fibrogenesis was also highlighted. Finally, available agonists inhibitors regulating these their application preventing were discussed. In summary, elucidating specific druggable more selective candidate medicines may represent promising approach bright prospects

Язык: Английский

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FTO Sensitizes Oral Squamous Cell Carcinoma to Ferroptosis via Suppressing ACSL3 and GPX4

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(22), С. 16339 - 16339

Опубликована: Ноя. 15, 2023

Ferroptosis is a newly established form of regulated cell death characterized by intracellular lipid peroxidation and iron accumulation that may be promising cancer treatment strategy. However, the function therapeutic value ferroptosis in oral squamous carcinoma (OSCC) remain inadequately understood. In present study, we investigated biological role fat mass obesity-associated gene (FTO) context OSCC. We found OSCC had greater potential for ferroptosis, FTO associated with ferroptosis. Furthermore, higher expression sensitized cells to vitro vivo. Mechanistically, suppressed anti-ferroptotic factors, acyl-CoA synthetase long-chain family member 3 (ACSL3) glutathione peroxidase 4 (GPX4), demethylating m6A modification on mRNA ACSL3 GPX4 decreasing their stability. Taken together, our findings revealed promotes through regulation. Thus, activation high levels serve as target.

Язык: Английский

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ALKBH5‐Mediated RNA m⁶A Methylation Regulates the Migration, Invasion, and Proliferation of Rheumatoid Fibroblast‐Like Synoviocytes

Arthritis & Rheumatology, Год журнала: 2023, Номер 76(2), С. 192 - 205

Опубликована: Авг. 19, 2023

Objective Fibroblast‐like synoviocytes (FLSs) are critical for promoting joint damage in rheumatoid arthritis (RA). N 6 ‐methyladenosine (m A) modification plays key roles various diseases, but its role the pathogenesis of RA is largely unknown. Here, we investigate increased demethylase ALKBH5 promotion proliferation, migration, and invasion FLSs via regulating JARID2 expression. Methods expression was evaluated using real‐time quantitative polymerase chain reaction (RT‐qPCR) Western blot. 5‐ethynyl‐2′‐deoxyuridine, scratch wound healing, transwell assays were implemented to determine on FLS mobility, migration. Then, m A sequencing combined with RNA performed identify potential targets . immunoprecipitation pulldown then used validate interaction between protein messenger (mRNA). Collagen‐induced (CIA) delayed‐type hypersensitivity (DTHA) models further established assess therapeutic potency vivo. Results We demonstrated that synovium from RA. Functionally, knockdown inhibited FLSs, whereas overexpression displayed opposite effect. Mechanistically, mediated mRNA enhanced stability cooperation IGF2BP3 Intriguingly, severity attenuated mice DTHA knockout or rats CIA intra‐articular injection short hairpin RNA. Conclusion Our findings suggest ‐mediated crucial synovial hyperplasia might be a target even dysregulated fibroblasts wide range diseases. image

Язык: Английский

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