The roles and implications of RNA m6A modification in cancer

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 20(8), С. 507 - 526

Опубликована: Май 23, 2023

Язык: Английский

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Exercise Mitigates Endothelial Pyroptosis and Atherosclerosis by Downregulating NEAT1 Through N6-Methyladenosine Modifications

Arteriosclerosis Thrombosis and Vascular Biology, Год журнала: 2023, Номер 43(6), С. 910 - 926

Опубликована: Апрель 20, 2023

The benefits of exercise on the cardiovascular system are widely recognized; however, underlying mechanisms unknown. Here, we report effect long noncoding RNA NEAT1 (nuclear paraspeckle assembly transcript 1), which is regulated by exercise, atherosclerosis development after N6-methyladenosine (m6A) modifications.Using clinical cohorts and NEAT1-/- mice, determined exercise-mediated expression role in atherosclerosis. To investigate mechanism epigenetic modification identified METTL14 (methyltransferase-like 14)-a key m6A enzyme under exercise-and found that alters through elucidated specific vitro vivo. Finally, downstream regulatory network was investigated.We downregulated with downregulation an important factor improvement exercise. Exercise-mediated loss function can delay Mechanistically, showed induced a significant METTL14, binds to sites promotes subsequent YTHDC1 (YTH domain-containing 1) recognition promote endothelial pyroptosis. Furthermore, induces pyroptosis binding KLF4 (Kruppel-like 4) transcriptional activation pyroptotic protein NLRP3 (NOD-like receptor thermal domain-associated 3), whereas attenuate NEAT1-mediated improve atherosclerosis.Our study provides new insights into This finding demonstrates while expanding our understanding regulates modifications.

Язык: Английский

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Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential

Biomarker Research, Год журнала: 2023, Номер 11(1)

Опубликована: Июнь 6, 2023

N6-methyladenosine (m6A) is the most prevalent and well-characterized internal chemical modification in eukaryotic RNA, influencing gene expression phenotypic changes by controlling RNA fate. Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) preferentially function as m6A effector proteins, promoting stability translation of m6A-modified RNAs. IGF2BPs, particularly IGF2BP1 IGF2BP3, are widely recognized oncofetal predominantly expressed cancer rather than normal tissues, playing a critical role tumor initiation progression. Consequently, IGF2BPs hold potential for clinical applications serve good choice targeted treatment strategies. In this review, we discuss functions mechanisms readers explore therapeutic targeting human cancer.

Язык: Английский

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A lncRNA signature associated with tumor immune heterogeneity predicts distant metastasis in locoregionally advanced nasopharyngeal carcinoma

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Май 30, 2022

Abstract Increasing evidence has revealed the roles of long noncoding RNAs (lncRNAs) as tumor biomarkers. Here, we introduce an immune-associated nine-lncRNA signature for predicting distant metastasis in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). The nine lncRNAs are identified through microarray profiling, followed by RT–qPCR validation and selection using a machine learning method training cohort ( n = 177). This classifies patients into high low risk groups, which have significantly different metastasis-free survival. Validations Guangzhou internal 177) Guilin external 150) cohorts yield similar results, confirming that is independent factor outperforms anatomy-based metrics identifying with metastatic risk. Integrative analyses show this correlates immune activity lymphocyte infiltration, validated digital pathology. Our results suggest can serve promising biomarker prediction LA-NPC.

Язык: Английский

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circPDE5A regulates prostate cancer metastasis via controlling WTAP-dependent N6-methyladenisine methylation of EIF3C mRNA

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Июнь 2, 2022

Circular RNA (circRNA) is a novel class noncoding (ncRNA) that plays critical role in various cancers, including prostate cancer (PCa). However, the clinical significance, biological function, and molecular mechanisms of circRNAs remain to be elucidated.A circRNA array was performed identified differentially expressed circRNAs. circPDE5A as which downregulated samples. Functionally, vitro vivo assays were applied explore PCa metastasis. Mechanistically, interaction between WTAP verified using pulldown followed by mass spectrometry, Immunoprecipitation (RIP) assays. m6A methylated immunoprecipitation sequencing (MeRIP-seq) then used downstream target circPDE5A. Chromatin assay (ChIP) dual-luciferase reporter transcriptional factor regulated expression.circPDE5A tissues compared adjacent normal tissue negatively correlated with gleason score patients. inhibits cells migration invasion both vivo. blocks WTAP-dependent N6-methyladenisine (m6A) methylation eukaryotic translation initiation 3c (EIF3C) mRNA forming circPDE5A-WTAP complex, finally disrupts EIF3C. Moreover, circPDE5A-dependent decrease EIF3C expression inactivates MAPK pathway restrains progression.Our findings demonstrate FOXO4-mediated upregulation controls metastasis via circPDE5A-WTAP-EIF3C-MAPK signaling could serve potential therapeutic targer for PCa.

Язык: Английский

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The roles of N6-methyladenosine and its target regulatory noncoding RNAs in tumors: classification, mechanisms, and potential therapeutic implications

Experimental & Molecular Medicine, Год журнала: 2023, Номер 55(3), С. 487 - 501

Опубликована: Март 1, 2023

Abstract N6-methyladenosine (m6A) is one of the epigenetic modifications RNA. The addition this chemical mark to RNA molecules regulates gene expression by affecting fate molecules. This posttranscriptional modification reversible and regulated methyltransferase “writers” demethylase “erasers”. m6A-modified RNAs depends on function different “readers” that recognize bind them. Research m6A methylation has recently increased due its important role in regulating cancer progression. Noncoding (ncRNAs) are a class transcribed from genome but whose roles have been overlooked their lack well-defined potential for translation into proteins or peptides. However, misconception now completely overturned. ncRNAs regulate various diseases, especially tumors, it confirmed they play either tumor-promoting tumor-suppressing almost all types tumors. In review, we discuss ncRNA summarize mechanisms involved. Finally, progress research clinical treatment significance

Язык: Английский

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WTAP-mediated m6A modification modulates bone marrow mesenchymal stem cells differentiation potential and osteoporosis

Cell Death and Disease, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 17, 2023

Abstract An imbalance in the differentiation potential of bone marrow mesenchymal stem cells (BMSCs) is an important pathogenic mechanism underlying osteoporosis (OP). N6-methyladenosine (m 6 A) most common post-transcriptional modification eukaryotic cells. The role Wilms’ tumor 1-associated protein (WTAP), a member m A functional family, regulating BMSCs remains unknown. We used patient-derived and mouse model-derived samples, qRT-PCR, western blot assays, ALP activity assay, ALP, Alizarin Red staining to determine changes mRNA levels genes proteins associated with differentiation. Histological analysis micro-CT were evaluate developmental bone. results determined that WTAP promoted osteogenic inhibited adipogenic BMSCs. co-immunoprecipitation (co-IP), RNA immunoprecipitation (RIP), methylated (MeRIP), pulldown, dual-luciferase assay explore direct mechanism. Mechanistically, expression increased during significantly pri-miR-181a pri-miR-181c methylation, which was recognized by YTHDC1, maturation miR-181a miR-181c. MiR-181a miR-181c SFRP1, promoting Our demonstrated WTAP/YTHDC1/miR-181a miR-181c/SFRP1 axis regulated fate BMSCs, suggesting it might be therapeutic target for osteoporosis.

Язык: Английский

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RNA modification in cardiovascular disease: implications for therapeutic interventions

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Окт. 27, 2023

Abstract Cardiovascular disease (CVD) is the leading cause of death in world, with a high incidence and youth-oriented tendency. RNA modification ubiquitous indispensable cell, maintaining cell homeostasis function by dynamically regulating gene expression. Accumulating evidence has revealed role aberrant expression CVD caused dysregulated modification. In this review, we focus on nine common modifications: N 6 -methyladenosine (m A), 1 5-methylcytosine 5 C), 7 -methylguanosine G), 4 -acetylcytosine (ac pseudouridine (Ψ), uridylation, adenosine-to-inosine (A-to-I) editing, modifications U34 tRNA wobble. We summarize key regulators their effects expression, such as splicing, maturation, transport, stability, translation. Then, based classification CVD, mechanisms which occurs progresses through are discussed. Potential therapeutic strategies, therapy, reviewed these mechanisms. Herein, some (such stroke peripheral vascular disease) not included due to limited availability literature. Finally, prospective applications challenges discussed for purpose facilitating clinical Moreover, look forward more studies exploring roles future, there substantial uncultivated areas be explored.

Язык: Английский

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Epigenetically silenced lncRNA SNAI3-AS1 promotes ferroptosis in glioma via perturbing the m6A-dependent recognition of Nrf2 mRNA mediated by SND1

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Май 19, 2023

Abstract Background Ferroptosis has been linked to tumor progression and resistance antineoplastic therapy. Long noncoding RNA (lncRNA) exerts a regulatory role in various biological processes of cells, while the function molecular mechanism lncRNA ferroptosis are yet be clarified glioma. Methods Both gain-of-function loss-of-function experiments were employed investigate effects SNAI3-AS1 on tumorigenesis susceptibility glioma vitro vivo. Bioinformatics analysis, Bisulfite sequencing PCR, pull-down, RIP, MeRIP dual-luciferase reporter assay performed explore low expression downstream Results We found that inducer erastin downregulates by increasing DNA methylation level promoter. functions as suppressor Importantly, enhances anti-tumor activity promoting both Mechanistically, competitively binds SND1 perturbs m 6 A-dependent recognition Nrf2 mRNA 3’UTR SND1, thereby reducing stability Nrf2. Rescue confirmed overexpression silence can rescue gain- ferroptotic phenotypes SNAI3-AS1, respectively. Conclusions Our findings elucidate effect detailed SNAI3-AS1/SND1/Nrf2 signalling axis ferroptosis, provide theoretical support for inducing improve treatment.

Язык: Английский

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KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo–YAP pathway

Cellular & Molecular Biology Letters, Год журнала: 2023, Номер 28(1)

Опубликована: Апрель 19, 2023

N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, function m6A modification mediated KIAA1429 [alias virus-like methyltransferase-associated protein (VIRMA)] during progression diffuse large B-cell lymphoma (DLBCL) remains undefined.The expression and clinical significance were verified our data. CRISPR/Cas9 deletion, CRISPR/dCas9-VP64 for activating endogenous was used evaluate its function. RNA sequencing (RNA-seq), methylated immunoprecipitation (MeRIP-seq), (RIP) assays, luciferase activity assay, stability experiments, co-immunoprecipitation performed investigate regulatory mechanism DLBCL. Tumor xenograft models established vivo experiments.Dysregulated regulators observed, a novel predictive model based on score Additionally, elevated associated with poor prognosis patients Knockout repressed DLBCL cell proliferation, facilitated cycle arrest G2/M phase, induced apoptosis vitro, inhibited tumor growth vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) identified as downstream KIAA1429, which CHST11 mRNA then recruited YTHDF2 reducing expression. Inhibition diminished MOB1B expression, resulting inactivation Hippo-YAP signaling, reprogramming Hippo genes.Our results revealed new pathway is inactivated KIAA1429/YTHDF2-coupled epitranscriptional repression CHST11, highlighting potential biomarker therapeutic progression.

Язык: Английский

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