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m 6 A regulators in GC cell Different m 6 A regulators have been confirmed to get involved in the process and molecular functions of RNA m 6 A modification in GC. Writers (including METTL3, METTL14, WTAP, RBM15, et al) and erasers (including FTO, ALKBH1, ALKBH5) make RNA m 6 A modification a dynamic and reversible process in GC cells. And readers are responsible for different downstream effects of m 6 A in GC cells, such as (a) HuR, IGF2BP1, IGF2BP2 and IGF2BP3 in the nucleus facilitate the proliferation, metastasis, or EMT program of GC cells by promoting target mRNA stability; (b) DGCR8 facilitates processing of m 6 A modified pri-miR-17-92, which promotes the proliferation of GC cells; (c) The deficiency of YTHDF1, which regulates FZD7 and USP14 translation, inhibits the proliferation and metastasis of GC cells; (d) YTHDF2 in the cytoplasm enhances GC cell proliferation, migration and invasion by promoting PTEN mRNA decay.
Source publication
The relationship between epitranscriptomics and malignant tumours has become a popular research topic in recent years. N6-methyladenosine (m6A), the most common post-transcriptional modification in mammals, is involved in various physiological processes in different cancer types, including gastric cancer (GC). The incidence and mortality of GC have...
Context in source publication
Context 1
... readers have been reported to have different biological functions in GC, which makes it difficult to determine the clinical value of readers as biomarkers. The functions of GC-related m 6 A readers, as well as their target RNAs, are explained in detail in Chapter 3 and shown in Figure 1. ...
Citations
... most abundant RNA modification in eukaryotic cells, plays a crucial role in tumorigenesis 15,16 . The expression of regulatory proteins associated with m 6 A is abnormal in most tumors, leading to drug resistance and tumor development 17,18 . METTL16, followed by classic METTL3/ METTL14 methyltransferases 19,20 , was recently identified as a second m 6 A writer 21 . ...
Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying the initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that copper content is significantly elevated in gastric cancer (GC), especially in malignant tumors. Screening reveals that METTL16, an atypical methyltransferase, is a critical mediator of cuproptosis through the m⁶A modification on FDX1 mRNA. Furthermore, copper stress promotes METTL16 lactylation at site K229 followed by cuproptosis. The process of METTL16 lactylation is inhibited by SIRT2. Elevated METTL16 lactylation significantly improves the therapeutic efficacy of the copper ionophore– elesclomol. Combining elesclomol with AGK2, a SIRT2-specific inhibitor, induce cuproptosis in gastric tumors in vitro and in vivo. These results reveal the significance of non-histone protein METTL16 lactylation on cuproptosis in tumors. Given the high copper and lactate concentrations in GC, cuproptosis induction becomes a promising therapeutic strategy for GC.
... N6-methyladenosine (m6A) modification is the most prevalent post-transcriptional modification in mammals, occurring in nearly 0.1-0.4% of adenosines, accounting for approximately 50% of all methylated ribonucleosides [11]. Over 80% of m6A modifications appear in messenger RNA (mRNA) and are mainly detected in the consensus sequence RRACH (R = A or G and H = A, C, or U) near transcript termination codons and 3′ untranslated regions (3′ UTRs) [12,13]. ...
Background
Disruption of N6 methyl adenosine (m6A) modulation hampers gene expression and cellular functions, leading to various illnesses. However, the role of m6A modification in osteoarthritis (OA) synovitis remains unclear. This study aimed to explore the expression patterns of m6A regulators in OA synovial cell clusters and identify key m6A regulators that mediate synovial macrophage phenotypes.
Methods
The expression patterns of m6A regulators in the OA synovium were illustrated by analyzing bulk RNA-seq data. Next, we built an OA LASSO-Cox regression prediction model to identify the core m6A regulators. Potential target genes of these m6A regulators were identified by analyzing data from the RM2target database. A molecular functional network based on core m6A regulators and their target genes was constructed using the STRING database. Single-cell RNA-seq data were collected to verify the effects of m6A regulators on synovial cell clusters. Conjoint analyses of bulk and single-cell RNA-seq data were performed to validate the correlation between m6A regulators, synovial clusters, and disease conditions. After IGF2BP3 was screened as a potential modulator in OA macrophages, the IGF2BP3 expression level was tested in OA synovium and macrophages, and its functions were further tested by overexpression and knockdown in vitro.
Results
OA synovium showed aberrant expression patterns of m6A regulators. Based on these regulators, we constructed a well-fitting OA prediction model comprising six factors (FTO, YTHDC1, METTL5, IGF2BP3, ZC3H13, and HNRNPC). The functional network indicated that these factors were closely associated with OA synovial phenotypic alterations. Among these regulators, the m6A reader IGF2BP3 was identified as a potential macrophage mediator. Finally, IGF2BP3 upregulation was verified in the OA synovium, which promoted macrophage M1 polarization and inflammation.
Conclusions
Our findings revealed the functions of m6A regulators in OA synovium and highlighted the association between IGF2BP3 and enhanced M1 polarization and inflammation in OA macrophages, providing novel molecular targets for OA diagnosis and treatment.
... In another biomarker study, Eyileten et al. identified and validated microRNAs with a role in ACE2-related thrombosis in coronavirus infection, which could serve as novel, thrombosis-related predictive biomarkers for COVID-19 complications and could be used for early patient stratification [15]. Besides altered RNA expression levels, one should also consider the alternative splicing as well as chemical modification and editing of RNA as exemplified in studies by Shizhi Wang et al., Amweg et al. and Xu et al. [16][17][18]. This will allow us to take full advantage of the diagnostic and prognostic potential of coding and non-coding RNAs in the future. ...
... Therefore, the interaction between m 6 A modification and lncRNA is a novel research direction for the treatment of MSI-positive GC (166). When compared with chemotherapy and targeted therapy, immunotherapy not only improves the living environment of patients with advanced cancer but also avoids drug resistance (167). As a result, elucidating the regulatory role of m 6 A in the diagnosis, treatment, and prognosis of GC can enable GC patients to achieve a longer survival time. ...
... The possible mechanism is that FTO reduces the levels of m 6 A in PD-1 and prevents YTHDF2-mediated PD-1 RNA decay. In addition, in vitro experiments revealed that blocking YTHDF1 improved the therapeutic effect of anti-PD-L1 in GC cells, and the knockout of m 6 A demethylase AlKBH5 makes tumor sensitive to anti PD-1 immunotherapy and changes immune cell recruitment (167,169). In order to improve the efficacy of immunotherapy, it is urgent to understand the tumor microenvironment (TME) and determine the mechanism behind the low response rate of ICB. ...
N6-methyladenosinen (m⁶A) methylation is a frequent RNA methylation modification that is regulated by three proteins: “writers”, “erasers”, and “readers”. The m⁶A modification regulates RNA stability and other mechanisms, including translation, cleavage, and degradation. Interestingly, recent research has linked m⁶A RNA modification to the occurrence and development of cancers, such as hepatocellular carcinoma and non-small cell lung cancer. This review summarizes the regulatory role of m⁶A RNA modification in gastric cancer (GC), including targets, the mechanisms of action, and the potential signaling pathways. Our present findings can facilitate our understanding of the significance of m⁶A RNA modification in GC.
Globally, gastric cancer (GC) is a major cause of cancer death. This study is aimed at investigating the biological functions of activating transcription factor 2 (ATF2) and the underlying mechanism in GC. In the present work, GEPIA, UALCAN, Human Protein Atlas and StarBase databases were adopted to analyze ATF2 expression characteristics in GC tissues and normal gastric tissues, and its relationships with tumor grade and patients' survival time. Quantitative real-time polymerase chain reaction (qRT-PCR) method was employed to examine ATF2 mRNA expression in normal gastric tissues, GC tissues, and GC cell lines. Cell counting kit-8 (CCK-8) and EdU assays were utilized for detecting GC cell proliferation. Cell apoptosis was detected by flow cytometry. PROMO database was applied to predict the binding site of ATF2 with the METTL3 promoter region. The binding relationship between ATF2 and the METTL3 promoter region was verified through dual-luciferase reporter gene assay and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assay. Western blot was performed to evaluate the effect of ATF2 on METTL3 expression. METTL3-related signaling pathways were predicted using Gene Set Enrichment Analysis (GSEA) in the LinkedOmics database. It was found that, ATF2 level was elevated in GC tissues and cell lines in comparison with normal tissues and correlated with short patients' survival time. ATF2 overexpression facilitated GC cell growth and suppressed the apoptosis, whereas ATF2 knockdown suppressed GC cell proliferation and facilitated the apoptosis. ATF2 bound to the METTL3 promoter region, and ATF2 overexpression promoted the transcription of METTL3, and ATF2 knockdown restrained the transcription of METTL3. METTL3 was associated with cell cycle progression, and ATF2 overexpression enhanced cyclin D1 expression, and METTL3 knockdown reduced cyclin D1 expression. In summary, ATF2 facilitates GC cell proliferation and suppresses the apoptosis via activating the METTL3/cyclin D1 signaling pathway, and ATF2 is promising to be an anti-drug target for GC.
