The role of m6A RNA methylation in cancer metabolism.
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ABSTRACT:
SUBMITTER: An Y
PROVIDER: S-EPMC8753874 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:N6-methyladenosine (m6A) is the most abundant internal modification of RNA in eukaryotic cells, and, in recent years, it has gained increasing attention. A good amount of data support the involvement of m6A modification in tumorigenesis, tumor progression, and metastatic dissemination. However, the role of this RNA modification in thyroid cancer still remains poorly investigated. In this study, m6A-related RNA methylation profiles are compared between a normal thyroid cell line and different thyroid cancer cell lines. With this approach, it was possible to identify the different patterns of m6A modification in different thyroid cancer models. Furthermore, by silencing METTL3, which is the main player in the RNA methylation machinery, it was possible to evaluate the impact of m6A modification on gene expression in an anaplastic thyroid cancer model. This experimental approach allowed us to identify DDI2 as a gene specifically controlled by the m6A modification in anaplastic thyroid cancer cell lines. Altogether, these data are a proof of concept that RNA methylation widely occurs in thyroid cancer cell models and open a way forward in the search for new molecular patterns for diagnostic discrimination between benign and malignant lesions.
| S-EPMC9569446 | biostudies-literature
Project description:Gastric cancer (GC) is a malignancy with poor prognosis. NDUFA4 is reported to correlate with the progression of GC. However, its underlying mechanism in GC is unknown. Our study was to reveal the pathogenic mechanism of NDUFA4 in GC. NDUFA4 expression was explored in single-cell and bulk RNA-seq data as well as GC tissue microarray. Mitochondrial respiration and glycolysis were estimated by oxygen consumption rate and extracellular acidification rate, respectively. The interaction between NDUFA4 and METTL3 was validated by RNA immunoprecipitation. Flow cytometry was used to estimate cell cycle, apoptosis and mitochondrial activities. NDUFA4 was highly expressed in GC and its high expression indicated a poor prognosis. The knockdown of NDUFA4 could reduce cell proliferation and inhibit tumor growth. Meanwhile, NDUFA4 could promote glycolytic and oxidative metabolism in GC cells, whereas the inhibition of glycolysis suppressed the proliferation and tumor growth of GC. Besides, NDUFA4 inhibited ROS level and promoted MMP level in GC cells, whereas the inhibition of mitochondrial fission could reverse NDUFA4-induced glycolytic and oxidative metabolism and tumor growth of GC. Additionally, METTL3 could increase the m6A level of NDUFA4 mRNA via the m6A reader IGF2BP1 to promote NDUFA4 expression in GC cells. Our study revealed that NDUFA4 was increased by m6A methylation and could promote GC development via enhancing cell glycolysis and mitochondrial fission. NDUFA4 was a potential target for GC treatment.
| S-EPMC9385701 | biostudies-literature
Project description:N6‑methyladenosine (m6A) is the most prevalent and abundant type of internal post‑transcriptional RNA modification in eukaryotic cells. Multiple types of RNA, including mRNAs, rRNAs, tRNAs, long non‑coding RNAs and microRNAs, are involved in m6A methylation. The biological function of m6A modification is dynamically and reversibly mediated by methyltransferases (writers), demethylases (erasers) and m6A binding proteins (readers). The methyltransferase complex is responsible for the catalyzation of m6A modification and is typically made up of methyltransferase‑like (METTL)3, METTL14 and Wilms tumor 1‑associated protein. Erasers remove methylation by fat mass and obesity‑associated protein and ALKB homolog 5. Readers play a role through the recognition of m6A‑modified targeted RNA. The YT521‑B homology domain family, heterogeneous nuclear ribonucleoprotein and insulin‑like growth factor 2 mRNA‑binding protein serve as m6A readers. The m6A methylation on transcripts plays a pivotal role in the regulation of downstream molecular events and biological functions, such as RNA splicing, transport, stability and translatability at the post‑transcriptional level. The dysregulation of m6A modification is associated with cancer, drug resistance, virus replication and the pluripotency of embryonic stem cells. Recently, a number of studies have identified aberrant m6A methylation in cardiovascular diseases (CVDs), including cardiac hypertrophy, heart failure, arterial aneurysm, vascular calcification and pulmonary hypertension. The aim of the present review article was to summarize the recent research progress on the role of m6A modification in CVD and give a brief perspective on its prospective applications in CVD.
| S-EPMC7595665 | biostudies-literature
Project description:BackgroundThe modification 6-methyladenine (m6 A) is the most common type in RNA methylation. Our study aims to explore the bioinformatic analysis of m6 A in endometrial cancer.MethodsThe expression of 23 m6 A RNA methylation regulators was compared through The Cancer Genome Atlas (TCGA) database among 406 endometrial tissue and 19 normal tissue samples. The Wilcoxon test was applied to compare the relationship between the clinicopathological characteristics and expression. Cox regressions were performed to identify the prognostic factors associated with overall survival. Gene ontology (GO) and Gene Set Enrichment Analysis (GSEA) were performed to evaluate the potential pathways.ResultsYTHDF2, HNRNPA2B1, HDRNPA2B1, YTHDF1, FMR1, IGF2BP3, METTL13, RBM15B, IGF2BP1, YTHDF3, YTHDC1, ZC3H13 IGF2BP2, KIAA1429, METTL14, RBMX, FTO, ALKBH5, and METTL16 were significantly abnormally expressed in endometrial cancer tissue samples. Both univariate and multivariate Cox regression analyses indicated that age, grade, and risk score were independent risk factors. High expression of FTO was associated with worse overall survival.ConclusionM6 A RNA methylation regulators play vital role in endometrial cancer.
| S-EPMC8418492 | biostudies-literature
Project description:N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m6A/m-seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m6A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.
| S-EPMC6069762 | biostudies-literature
Project description:m6A (N6-methyladenosine) methylation, a well-known modification in tumour epigenetics, dynamically and reversibly fine tunes the entire process of RNA metabolism. Aberrant levels of m6A and its regulators, which can predict the survival and outcomes of cancer patients, are involved in tumorigenesis, metastasis and resistance. Ovarian cancer (OC) ranks first among gynaecological tumours in the causes of death. At first diagnosis, patients with OC are usually at advanced stages owing to a lack of early biomarkers and effective targets. After treatment, patients with OC often develop drug resistance. This article reviews the recent experimental advances in understanding the role of m6A modification in OC, raising the possibility to treat m6A modification and its regulators as promising diagnostic markers and therapeutic targets for OC.
| S-EPMC8666073 | biostudies-literature
Project description:RNA N6-methyladenosine (m6A) methylation is known to be the most popular RNA modification in animals. Many research reports have elaborated on the effects of m6A regulators in medical practice, such as diagnosis, prognosis, and treatment. M6A modification has evident impacts on many aspects of RNA metabolism, just like RNA splicing, processing, translation, and stability. M6A also has a magnificent role in numerous types of cancers. We analyzed the prostate cancer datasets, from The Cancer Genome Atlas (TCGA) database, for every recognized m6A regulator in their gene expression, DNA methylation status and copy number variations (CNVs). We also systematically analyzed the relationship between different m6A regulators and the prognosis of prostate cancer. The results illustrated considerable differences in the expression of various m6A regulators between the prostate and normal cancer samples. At the same time, there were evident differences in the expression of various m6A regulators in prostate cancers with different Gleason scores. Subsequently, we determined CBLL1, FTO, YTHDC1, HNRNPA2B1 as crucial m6A regulators of prostate cancer. Premised on the expression of CBLL1, we also identified potential therapeutic agents for prostate cancer, and knockdown of HNRNPA2B1 prominently inhibited prostate cells migration and invasion in vitro experiment.
| S-EPMC8661905 | biostudies-literature
Project description:As the most prevalent and abundant transcriptional modification in the eukaryotic genome, the continuous and dynamic regulation of N6-methyladenosine (m6A) has been shown to play a vital role in physiological and pathological processes of cardiovascular diseases (CVDs), such as ischemic heart failure (HF), myocardial hypertrophy, myocardial infarction (MI), and cardiomyogenesis. Regulation is achieved by modulating the expression of m6A enzymes and their downstream cardiac genes. In addition, this process has a major impact on different aspects of internal biological metabolism and several other external environmental effects associated with the development of CVDs. However, the exact molecular mechanism of m6A epigenetic regulation has not been fully elucidated. In this review, we outline recent advances and discuss potential therapeutic strategies for managing m6A in relation to several common CVD-related metabolic disorders and external environmental factors. Note that an appropriate understanding of the biological function of m6A in the cardiovascular system will pave the way towards exploring the mechanisms responsible for the development of other CVDs and their associated symptoms. Finally, it can provide new insights for the development of novel therapeutic agents for use in clinical practice.
| S-EPMC7383322 | biostudies-literature
Project description:N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells, and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m6A modification in the hypoxic tumor microenvironment, and identifies FOXO3 as an important target of m6A modification in the resistance of HCC to sorafenib therapy.
| S-SCDT-EMBOJ-2019-103181 | biostudies-other
Project description:N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.
| S-EPMC7925544 | biostudies-literature