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N6-methyladenosine (m6A) plays a pivotal role in regulating epitranscriptomic mechanisms and is closely linked to the normal functioning of diverse classes of RNAs, both coding as well as noncoding. Recent research highlights the role of m6A RNA methylation in the onset and progression of several cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCC ranks as the seventh most common cancer globally, with a five-year patient survival rate of just 50%. Elevated m6A RNA methylation levels and deregulated expression of various m6A modifiers, i.e. writers, readers, and erasers, have been reported across nearly all HNSCC subtypes. Numerous studies have demonstrated that m6A modifications significantly impact key hallmarks of HNSCC, such as proliferation, apoptosis, migration, and invasion. Furthermore, m6A impacts epithelial-mesenchymal transition (EMT), drug resistance, and aerobic glycolysis, and disrupts the tumor microenvironment. Additionally, transcripts regulated by m6A in HNSCC present themselves as potential diagnostic and prognostic biomarkers. This review attempts to comprehensively summarize the role of m6A RNA methylation and its modifiers in regulating various facets of HNSCC pathogenesis. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is a prevalent and dynamic RNA modification, critical in regulating gene expression. Recent research has shed light on its significance in the life cycle of viruses, especially animal viruses. Depending on the context, these modifications can either enhance or inhibit the replication of viruses. However, research on m6A modifications in animal virus genomes and the impact of viral infection on the host cell m6A landscape has been hindered due to the difficulty of detecting m6A sites at a single-nucleotide level. This article summarises the methods for detecting m6A in RNA. It then discusses the progress of research into m6A modification within animal viruses' infections, such as influenza A virus, porcine epidemic diarrhoea virus, porcine reproductive, and respiratory syndrome virus. Finally, the review explores how m6A modification affects the following three aspects of the replication of animal RNA viruses: the regulation of viral genomic RNA function, the alteration of the m6A landscape in cells after viral infection, and the modulation of antiviral immunity through m6A modification. Research on m6A modifications in viral RNA sheds light on virus-host interactions at a molecular level. Understanding the impact of m6A on viral replication can help identify new targets for antiviral drug development and may uncover novel regulatory pathways that could potentially enhance antiviral immune responses. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) exerts many of its regulatory effects on eukaryotic mRNAs by recruiting cytoplasmic YT521-B homology-domain family (YTHDF) proteins. Here, we show that in Arabidopsis thaliana, the interaction between m6A and the major YTHDF protein ECT2 also involves the mRNA-binding ALBA protein family. ALBA and YTHDF proteins physically associate via a deeply conserved short linear motif in the intrinsically disordered region of YTHDF proteins and their mRNA target sets overlap, with ALBA4 binding sites being juxtaposed to m6A sites. These binding sites correspond to pyrimidine-rich elements previously found to be important for m6A binding to ECT2. Accordingly, both the biological functions of ECT2, and its binding to m6A targets in vivo, require ALBA association. Our results introduce the YTHDF-ALBA complex as the functional cytoplasmic m6A-reader in Arabidopsis, and define a molecular foundation for the concept of facilitated m6A reading, which increases the potential for combinatorial control of biological m6A effects. Synopsis: YTHDF proteins read the m6A-code on eukaryotic mRNA in the cytoplasm. This report shows that in Arabidopsis, m6A is read not simply by YTHDF proteins, but by their complexes with the ancient RNA-binding ALBA proteins. A short linear motif (SLiM), deeply conserved in the intrinsically disordered region of plant m6A-binding YTHDF proteins, is required for their RNA-binding in vivo. This SLiM is necessary for physical association with the ALBA family of RNA-binding proteins. The ALBA protein ALBA4 binds to pyrimidine-rich elements juxtaposed to m6A in mRNA targets of the major YTHDF proteins ECT2 and ECT3. ALBA proteins are required for biological effects of m6A and for ECT2-binding to m6A targets in vivo. The plant m6A reader consists of a complex between ECT2/3 and the RNA-binding protein ALBA. [ABSTRACT FROM AUTHOR]

Background: N6‐methyladenosine (m6A) modification is a widespread and reversible epigenetic alteration in eukaryotic mRNA, playing a pivotal role in various biological functions. Its significance in female reproductive development and associated diseases has recently become a focal point of research. Objective: This review aims to consolidate current knowledge of the role of m6A modification in female reproductive tissues, emphasizing its regulatory dynamics, functional significance, and implications in reproductive health and disease. Methods: A comprehensive analysis of recent studies focusing on m6A modification in ovarian development, oocyte maturation, embryo development, and the pathogenesis of reproductive diseases. Results: m6A modification exhibits dynamic regulation in female reproductive tissues, influencing key developmental stages and processes. It plays critical roles in ovarian development, oocyte maturation, and embryo development, underpinning essential aspects of reproductive health. m6A modification is intricately involved in the pathogenesis of several reproductive diseases, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), and endometriosis, offering insights into potential molecular mechanisms and therapeutic targets. Conclusion: The review highlights the crucial role of m6A modification in female reproductive development and related diseases. It underscores the need for further research to explore innovative diagnostic and therapeutic strategies for reproductive disorders, leveraging the insights gained from understanding m6A modification's impact on reproductive health. [ABSTRACT FROM AUTHOR]

Epilepsy is a common neurological disorder which can cause significant morbidity and mortality. N6-methyladenosine (m6A), the most common chemical epigenetic modification among mRNA post-transcriptional modifications, implicated in various physiological and pathological processes, but its role in epilepsy is still unknown. Here, we provide strong evidences in support of an association of m6A and its regulatory proteins with epilepsy. Our results indicated that the level of m6A was declined significantly in the dentate gyrus (DG) of hippocampus of pentylenetetrazol (PTZ)-induced seizure mice. Both the seizure-like behaviors and the excessive activation of DG area neuron were significantly mitigated after the administration of m6A agonist betaine. Mechanically, we found that both the m6A methyltransferase METTL14 and recognition protein YTHDC1 were decreased by PTZ stimulation, which might contribute to the reduced m6A level. Additionally, DG-specific over-expression of METTL14 or YTHDC1 by lentivirus injection could significantly ameliorate seizure-like behaviors and prevent the excessive activation of neuron in epilepsy mice induced by PTZ injection, which might be due to the normalized m6A level. Together, this study identified that METTL14/YTHDC1-mediated m6A modification could participate in seizure-like behaviors, which might provide m6A regulation as a potential and novel therapeutic strategy for epilepsy. [ABSTRACT FROM AUTHOR]

RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of 'writers', 'readers' and 'erasers' which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these 'readers', 'writers', and 'erasers' is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential. M6A RNA modifications: emerging drivers of leukemia growth and progression. [ABSTRACT FROM AUTHOR]

Background: Cardiac fibrosis is common in myocardial infarction (MI), leading to progressive cardiac dysfunction. Studies suggested that the abnormal N6-methyladenosine (m6A) modification induced by fat mass and obesity protein (FTO) is vital in MI. However, the effects of FTO on post-infarction cardiac fibrosis have not been detected. Methods: Western blot and quantitative real-time PCR were performed to detect the expression of FTO in the fibrotic tissue of rats. The functions of FTO on collagen biosynthesis were analyzed in vitro and in vivo. The underlying targets of FTO were selected through RNA-seq with m6A-seq. The following dual luciferase reporter assay and RNA stability assay were conducted to investigate the mechanisms of FTO-mediated m6A regulation. Results: The expression of FTO was decreased in the fibrotic tissue of post-infarction rats. The HIF-1 signal pathway was enriched after MI. HIF-1α could bind to the promoter of FTO and inhibit its expression. Functionally, FTO inhibited collagen synthesis after MI in vitro and in vivo. Mechanistically, EPRS was selected as the underlying target of FTO-induced m6A regulation. IGF2BP3 recognized and bound to the m6A sites of EPRS mRNA, which improved its stability. EPRS was required for cardiac fibrosis induced by FTO silencing. Conclusions: FTO, identified as a cardioprotective factor, suppressed collagen synthesis in post-infarction cardiac fibrosis via m6A modification, which provided a new therapeutic strategy for cardiac fibrosis. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6‐methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T‐cell function and enhancing anti‐tumour immunity remains unexplored. Methods: Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA‐seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single‐cell RNA‐seq (scRNA‐seq). Furthermore, in vitro and in vivo T‐cell cytotoxicity killing assay and CRISPR Cas9‐mediated m6A reader YTHDF1‐3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells. Results: We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T‐cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti‐tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)‐I degradation. Remarkably, these anti‐tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon‐gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T‐cell killing ability, and concurrently dampening the expression of exhaustion‐related genes. Conclusion: Targeting METTL3 enhances anti‐tumour immunity by boosting T‐cell cytotoxicity and reversing T‐cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti‐tumour defenses and overcome immune resistance. Key points: Targeting METTL3 augments tumour cell immunogenicity and sustains T‐cell function.T cell with METTL3 inhibition can reverse T‐cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti‐PD‐1 therapy.YTHDF2 deletion in tumours prolong the lifespan of MHC‐I mRNAs. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) is an abundant RNA epitranscriptomic modification in eukaryotes. The m6A machinery includes cellular writer, eraser and reader proteins that regulate m6A. Pteropus alecto (P. alecto) (the Australian black flying fox) and Rousettus aegyptiacus (R. aegyptiacus) (the Egyptian fruit bat) are bats associated with several viral zoonoses yet neglected in the field of m6A epigenetics studies. Objectives: This study utilises various bioinformatics and in silico tools to genetically identify, characterise and annotate the m6A machinery in P. alecto and R. aegyptiacus. Methods: A range of bioinformatic tools were deployed to comprehensively characterise all known m6A-associated proteins of P. alecto and R. aegyptiacus. Results: Phylogenetically, the m6A fat mass and obesity-associated protein (FTO) eraser placed the order Chiroptera (an order including all bat species) in a separate clade. Additionally, it showed the lowest identity matrices in P. alecto and R. aegyptiacus when compared to other mammals (74.1% and 72.8%) and Homo sapiens (84.0% and 76.1%), respectively. When compared to humans, genetic loci-based analysis of P. alecto and R. aegyptiacus showed syntenic conservation in multiple flanking genes of 8 out the 10 m6A-associated genes. Furthermore, amino acid alignment and protein tertiary structure of the two bats' m6A machinery demonstrated conservation in the writers but not in erasers and readers, compared to humans. Conclusions: These studies provide foundational annotation and genetic characterisation of m6A machinery in two important species of bats which can be exploited to study bat–virus interactions at the interface of epitranscriptomics. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac fibrosis is common in myocardial infarction (MI), leading to progressive cardiac dysfunction. Studies suggested that the abnormal N 6-methyladenosine (m6A) modification induced by fat mass and obesity protein (FTO) is vital in MI. However, the effects of FTO on post-infarction cardiac fibrosis have not been detected. Methods Western blot and quantitative real-time PCR were performed to detect the expression of FTO in the fibrotic tissue of rats. The functions of FTO on collagen biosynthesis were analyzed in vitro and in vivo. The underlying targets of FTO were selected through RNA-seq with m6A-seq. The following dual luciferase reporter assay and RNA stability assay were conducted to investigate the mechanisms of FTO-mediated m6A regulation. Results The expression of FTO was decreased in the fibrotic tissue of post-infarction rats. The HIF-1 signal pathway was enriched after MI. HIF-1α could bind to the promoter of FTO and inhibit its expression. Functionally, FTO inhibited collagen synthesis after MI in vitro and in vivo. Mechanistically, EPRS was selected as the underlying target of FTO-induced m6A regulation. IGF2BP3 recognized and bound to the m6A sites of EPRS mRNA, which improved its stability. EPRS was required for cardiac fibrosis induced by FTO silencing. Conclusions FTO, identified as a cardioprotective factor, suppressed collagen synthesis in post-infarction cardiac fibrosis via m6A modification, which provided a new therapeutic strategy for cardiac fibrosis.

Abstract Breast cancer is the most common cancer type among women. Despite advanced treatment strategies, some patients still face challenges in disease control, prompting the exploration of new therapeutic approaches. N6-Methyladenosine (m6A) methylation modification regulates RNA and plays a crucial role in various tumor biological processes, closely linked to breast cancer occurrence, development, prognosis, and treatment. M6A regulators impact breast cancer progression, development, and drug resistance by modulating RNA metabolism and tumor-related pathways. Researchers have begun to understand the regulatory mechanisms of m6A methylation in breast cancer. This paper discusses the roles of m6A regulators in breast cancer progression, prognosis, and treatment, offering new perspectives for breast cancer diagnosis and treatment.

Myeloid-derived suppressor cells (MDSCs) are closely related to the occurrence and development of many cancers, but the specific mechanism is not fully understood. It has been found that N6-methyladenosine (m6A) plays a key role in RNA metabolism, but its function in MDSCs has yet to be revealed. In this study, we found that MDSCs in mice with colorectal cancer (CRC) have significantly elevated levels of m6A, while ALKBH5 expression is decreased. Overexpression of ALKBH5 can reduce the immunosuppressive function of MDSCs in vivo and in vitro, and attenuates the protumorigenic ability of MDSCs. Mechanism study found that the overexpression of ALKBH5 in MDSCs reduced the m6A modification level of Arg-1 mRNA, and then weakened the stability of Arg-1 mRNA and protein expression. These data suggest that the decreased expression of ALKBH5 in CRC tumor mice may promote the expression of Arg-1, enhance the immunosuppressor function of MDSCs, and promote tumor growth. These findings highlight that ALKBH5 may regulate the function of MDSCs in tumor-bearing mice and may be a new target for immunotherapy. This research provides a new perspective for our understanding of the role of MDSCs in cancer development, and also brings new hope for cancer treatment.

Abstract Background N6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown. Objectives This study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging. Methods m6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay. Results m6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process. Conclusions The increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging.

Abstract N6-methyladenosine (m6A) is dynamically regulated by methyltransferases (termed “writers”) and demethylases (referred to as “erasers”), facilitating a reversible modulation. Changes in m6A levels significantly influence cellular functions, such as RNA export from the nucleus, mRNA metabolism, protein synthesis, and RNA splicing. They are intricately associated with a spectrum of pathologies. Moreover, dysregulation of m6A modulation has emerged as a promising therapeutic target across many diseases. m6A plays a pivotal role in controlling vital downstream molecules and critical biological pathways, contributing to the pathogenesis and evolution of numerous conditions. This review provides an overview of m6A demethylases, explicitly detailing the structural and functional characteristics of FTO and ALKBH5. Additionally, we explore their distinct involvement in various diseases, examine factors regulating their expression, and discuss the progress in inhibitor development.

Breast cancer is the most common cancer type among women. Despite advanced treatment strategies, some patients still face challenges in disease control, prompting the exploration of new therapeutic approaches. N6-Methyladenosine (m6A) methylation modification regulates RNA and plays a crucial role in various tumor biological processes, closely linked to breast cancer occurrence, development, prognosis, and treatment. M6A regulators impact breast cancer progression, development, and drug resistance by modulating RNA metabolism and tumor-related pathways. Researchers have begun to understand the regulatory mechanisms of m6A methylation in breast cancer. This paper discusses the roles of m6A regulators in breast cancer progression, prognosis, and treatment, offering new perspectives for breast cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Kashin‐Beck disease (KBD) is a chronic degenerative, disabling disease of the bones and joints and its exact aetiology and pathogenesis remain uncertain. This study is to investigate the role of m6A modification in the pathogenesis of KBD. Combined analysis of m6A MeRIP‐Seq and RNA‐Seq were used to analyse human peripheral blood samples from three KBD patients and three normal controls (NC). Bioinformatic methods were used to analyse m6A‐modified differential genes and RT‐qPCR was performed to validate the mRNA expression of several KBD‐related genes. The results indicated that the total of 16,811 genes were modified by m6A in KBD group, of which 4882 genes were differential genes. A large number of differential genes were associated with regulation of transcription, signal transduction and protein binding. KEGG analysis showed that m6A‐enriched genes participated the pathways of Vitamin B6 metabolism, endocytosis and Rap 1 signalling pathway. There was a positive association between m6A abundance and levels of gene expression, that there were 6 hypermethylated and upregulated genes (hyper‐up), 23 hypomethylated and downregulated genes (hypo‐down) in KBD group compared with NC. In addition, the mRNA expression of levels of MMP8, IL32 and GPX1 were verified and the protein–protein interaction networks of these key factors were constructed. Our study showed that m6A modifications may play a vital role in modulating gene expression, which represents a new clue to reveal the pathogenesis of KBD. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) RNA methylation is a prevalent RNA modification that significantly impacts RNA metabolism and cancer development. Maintaining the global m6A levels in cancer cells relies on RNA accessibility to methyltransferases and the availability of the methyl donor S-adenosylmethionine (SAM). Here, we reveal that death associated protein 3 (DAP3) plays a crucial role in preserving m6A levels through two distinct mechanisms. First, although DAP3 is not a component of the m6A writer complex, it directly binds to m6A target regions, thereby facilitating METTL3 binding. Second, DAP3 promotes MAT2A's last intron splicing, increasing MAT2A protein, cellular SAM, and m6A levels. Silencing DAP3 hinders tumorigenesis, which can be rescued by MAT2A overexpression. This evidence suggests DAP3's role in tumorigenesis, partly through m6A regulation. Our findings unveil DAP3's complex role as an RNA-binding protein and tumor promoter, impacting RNA processing, splicing, and m6A modification in cancer transcriptomes. [ABSTRACT FROM AUTHOR]

Background: N6-Methyladenosine (m6A) methylation, a common form of RNA modification, play an important role in the pathogenesis of various diseases and in the ontogeny of organisms. Nevertheless, the precise function of m6A methylation in photoaging remains unknown. Objectives: This study aims to investigate the biological role and underlying mechanism of m6A methylation in photoaging. Methods: m6A dot blot, Real-time quantitative PCR (RT-qPCR), western blot and immunohistochemical (IHC) assays were employed to detect the m6A level and specific m6A methylase in ultraviolet ray (UVR)-induced photoaging tissue. The profile of m6A-tagged mRNA was identified by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis. Finally, we investigated the regulatory mechanism of KIAA1429 by MeRIP-qPCR, RNA knockdown and immunofluorescence assay. Results: m6A levels were increased in photoaging and were closely associated with the upregulation of KIAA1429 expression. 1331 differentially m6A methylated genes were identified in the UVR group compared with the control group, of which 1192 (90%) were hypermethylated. Gene ontology analysis showed that genes with m6A hypermethylation and mRNA downregulation were mainly involved in extracellular matrix metabolism and collagen metabolism-related processes. Furthermore, KIAA1429 knockdown abolished the downregulation of TGF-bRII and upregulation of MMP1 in UVR-irradiated human dermal fibroblasts (HDFs). Mechanically, we identified MFAP4 as a target of KIAA1429-mediated m6A modification and KIAA1429 might suppress collagen synthesis through an m6A-MFAP4-mediated process. Conclusions: The increased expression of KIAA1429 hinders collagen synthesis during UVR-induced photoaging, suggesting that KIAA1429 represents a potential candidate for targeted therapy to mitigate UVR-driven photoaging. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) modification involves the methylation of the sixth nitrogen atom on the base A of RNA molecules. It is the most common and abundant RNA epigenetic modification in eukaryotic organism. It could not only directly affect the transcriptional level of intracellular genome, but also regulate the expression level of oncogenes, tumor suppressor genes and some ncRNA genes. Additionally, some autophagy-related genes and ferroptosis metabolism pathway-related genes were also reported to be regulated by m6A. The abnormal regulation and dysfunction of target genes by m6A usually promote or inhibit the growth of tumor cells. Therefore, the regulation of cellular autophagy and ferroptosis by m6A to affect the growth of tumor was summarized in the study. It will be useful to demonstrate the mechanism of tumorigenesis and provide scientific basis for the development of a novel 6 target on the treatment of tumor. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is dynamically regulated by methyltransferases (termed "writers") and demethylases (referred to as "erasers"), facilitating a reversible modulation. Changes in m6A levels significantly influence cellular functions, such as RNA export from the nucleus, mRNA metabolism, protein synthesis, and RNA splicing. They are intricately associated with a spectrum of pathologies. Moreover, dysregulation of m6A modulation has emerged as a promising therapeutic target across many diseases. m6A plays a pivotal role in controlling vital downstream molecules and critical biological pathways, contributing to the pathogenesis and evolution of numerous conditions. This review provides an overview of m6A demethylases, explicitly detailing the structural and functional characteristics of FTO and ALKBH5. Additionally, we explore their distinct involvement in various diseases, examine factors regulating their expression, and discuss the progress in inhibitor development. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the most common cancers, with a high mortality rate worldwide. Mounting evidence indicates that mRNA modifications are crucial in RNA metabolism, transcription, processing, splicing, degradation, and translation. Studies show that N6-methyladenosine (m6A) is mammalians' most common epi-transcriptomic modification. It has been demonstrated that m6A is involved in cancer formation, progression, invasion, and metastasis, suggesting it could be a potential biomarker for CRC diagnosis and developing therapeutics. Cytokines, growth factors, and hormones function in JAK/STAT3/5 signaling pathway, and they could regulate the intestinal response to infection, inflammation, and tumorigenesis. Reports show that the JAK/STAT3/5 pathway is involved in CRC development. However, the underlying mechanism is still unclear. Signal Transducer and Activator of Transcription 3/5 (STAT3, STAT5) can act as oncogenes or tumor suppressors in the context of tissue types. Also, epigenetic modifications and mutations could alter the balance between pro- oncogenic and tumor suppressor activities of the STAT3/5 signaling pathway. Thus, exploring the interaction of cytokines-JAKs-STAT3 and/or STAT5 with mRNA m6A is of great interest. This review provides a comprehensive overview of the characteristics and functions of m6A and JAKs-STAT3/5 and their relationship with gastrointestinal (GI) cancers. [ABSTRACT FROM AUTHOR]

Background: N6‐methyladenosine (m6A) has been identified as the most abundant modification of RNA molecules and the aberrant m6A modifications have been associated with the development of autoimmune diseases. However, the role of m6A modification in ankylosing spondylitis (AS) has not been adequately investigated. Therefore, we aimed to explore the significance of m6A regulator‐mediated RNA methylation in AS. Methods: The methylated RNA immunoprecipitation sequencing (meRIP‐seq) and digital RNA sequencing (Digital RNA‐seq) were conducted using the peripheral blood mononuclear cells from three AS cases and three healthy controls, to identify genes affected by abnormal RNA methylation. The genes associated with different peaks were cross‐referenced with AS‐related genes obtained from the GeneCards Suite. Subsequently, the expression levels of shared differentially expressed genes (DEGs) and key m6A regulators in AS were evaluated using data from 68 AS cases and 36 healthy controls from two data sets (GSE25101 and GSE73754). In addition, the results were validated through quantitative polymerase chain reaction (qPCR). Results: The meRIP‐seq and Digital RNA‐seq analyses identified 28 genes with upregulated m6A peaks but with downregulated expression, and 52 genes with downregulated m6A peaks but with upregulated expression. By intersecting the genes associated with different peaks with 2184 AS‐related genes from the GeneCards Suite, we identified a total of five shared DEGs: BCL11B, KAT6B, IL1R1, TRIB1, and ALDH2. Through analysis of the data sets and qPCR, we found that BCL11B and IL1R1 were differentially expressed in AS. Moreover, two key m6A regulators, WTAP and heterogeneous nuclear ribonucleoprotein C, were identified. Conclusions: In conclusion, the current study revealed that m6A modification plays a crucial role in AS and might hence provide a new treatment strategy for AS disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Background N6‐methyladenosine (m6A) modification is a widespread and reversible epigenetic alteration in eukaryotic mRNA, playing a pivotal role in various biological functions. Its significance in female reproductive development and associated diseases has recently become a focal point of research. Objective This review aims to consolidate current knowledge of the role of m6A modification in female reproductive tissues, emphasizing its regulatory dynamics, functional significance, and implications in reproductive health and disease. Methods A comprehensive analysis of recent studies focusing on m6A modification in ovarian development, oocyte maturation, embryo development, and the pathogenesis of reproductive diseases. Results m6A modification exhibits dynamic regulation in female reproductive tissues, influencing key developmental stages and processes. It plays critical roles in ovarian development, oocyte maturation, and embryo development, underpinning essential aspects of reproductive health. m6A modification is intricately involved in the pathogenesis of several reproductive diseases, including polycystic ovary syndrome (PCOS), premature ovarian failure (POF), and endometriosis, offering insights into potential molecular mechanisms and therapeutic targets. Conclusion The review highlights the crucial role of m6A modification in female reproductive development and related diseases. It underscores the need for further research to explore innovative diagnostic and therapeutic strategies for reproductive disorders, leveraging the insights gained from understanding m6A modification's impact on reproductive health.

Thyroid cancer (TC) is the most common malignant tumor of the head and neck. As a common epigenetic modification in mRNAs, N6-methyladenosine (m6A) modification plays critical roles in biological process of cancers. However, m6A methyltransferase methyltransferase-like 14 (METTL14)-mediated m6A modification and its potential regulatory mechanisms in TC are not fully elucidated. In our study, we observed that METTL14 was decreased in TC tissues and cells. And upregulation of METTL14 induced apoptotic cell death and hampered cell proliferation, epithelial mesenchymal transition (EMT) and tumor growth in vitro and in vivo. Mechanistically, METTL14 increased the expression of suppressor of cytokine signaling 3 (SOCS3) through m6A methylation modification, and knockdown of SOCS3 reversed the inhibitory effect of overexpressing METTL14 on TC tumorigenesis. In addition, METTL14-mediated m6A modification of SOCS3 inactivated the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway, and in the METTL14-overexpressing TC cells, silencing SOCS3-induced upregulation of cell proliferation, EMT and suppression of apoptosis was reversed by JAK2/STAT3 inhibitor AG490 and WP1066. Together, we indicated that METTL14/m6A/SOCS3/JAK2/STAT3 axis play an important role in the progression of TC.

ABSTRACT Background Immunotherapy has emerged as a crucial treatment modality for solid tumours, yet tumours often evade immune surveillance. There is an imperative to uncover novel immune regulators that can boost tumour immunogenicity and increase the efficacy of immune checkpoint blockade (ICB) therapy. Epigenetic regulators play critical roles in tumour microenvironment remodelling, and N6‐methyladenosine (m6A) is known to be involved in tumourigenesis. However, the role of m6A in regulating T‐cell function and enhancing anti‐tumour immunity remains unexplored. Methods Several cancer cell lines were treated with STM2457, an enzymatic inhibitor of RNA m6A methyltransferase METTL3, and explored the transcriptome changes with RNA sequencing (RNA‐seq). We then utilised mouse melanoma (B16) and mouse colorectal adenocarcinoma (MC38) models to investigate the effects of METTL3 inhibition on immunotherapy, and analysed the dynamics of the tumour microenvironment via single‐cell RNA‐seq (scRNA‐seq). Furthermore, in vitro and in vivo T‐cell cytotoxicity killing assay and CRISPR Cas9‐mediated m6A reader YTHDF1‐3 knockout in B16 were performed to assess the role and the molecular mechanism of RNA m6A in tumour killing. Finally, the efficacy of METTL3 inhibition was also tested on human melanoma model (A375) and human T cells. Results We demonstrate that inhibiting METTL3 augments tumour immunogenicity and sustains T‐cell function, thereby enhancing responsiveness to ICB therapy. Mechanistically, METTL3 inhibition triggers an interferon response within tumour cells, amplifying the anti‐tumour immune response, along with deletion of the m6A reader protein YTHDF2 in tumours inhibiting major histocompatibility complex (MHC)‐I degradation. Remarkably, these anti‐tumour effects are reliant on the immune system. Specifically, METTL3 inhibition enhances interferon‐gamma (IFNγ) and granzyme B (GzmB) expression, thereby strengthening T‐cell killing ability, and concurrently dampening the expression of exhaustion‐related genes. Conclusion Targeting METTL3 enhances anti‐tumour immunity by boosting T‐cell cytotoxicity and reversing T‐cell exhaustion. Our study positions METTL3 as an epigenetic checkpoint, highlighting the potential of targeting METTL3 to invigorate intrinsic anti‐tumour defenses and overcome immune resistance. Key points Targeting METTL3 augments tumour cell immunogenicity and sustains T‐cell function. T cell with METTL3 inhibition can reverse T‐cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti‐PD‐1 therapy. YTHDF2 deletion in tumours prolong the lifespan of MHC‐I mRNAs.

RNA modification is the critical mechanism for regulating post-transcriptional processes. There are more than 150 RNA modifications reported so far, among which N6-Methyladenosine is the most prevalent one. M6A RNA modification complex consists of ‘writers’, ‘readers’ and ‘erasers’ which together in a group catalyze, recognize and regulate the methylation process of RNA and thereby regulate the stability and translation of mRNA. The discovery of erasers also known as demethylases, revolutionized the research on RNA modifications as it revealed that this modification is reversible. Since then, various studies have focused on discovering the role of m6A modification in various diseases especially cancers. Aberrant expression of these ‘readers’, ‘writers’, and ‘erasers’ is found to be altered in various cancers resulting in disturbance of cellular homeostasis. Acute leukemias are the most common cancer found in pediatric patients and account for 20% of adult cases. Dysregulation of the RNA modifying complex have been reported in development and progression of hematopoietic malignancies. Further, targeting m6A modification is the new approach for cancer immunotherapy and is being explored extensively. This review provides detailed information about current information on the role of m6A RNA modification in acute leukemia and their therapeutic potential.

Abstract miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3’-untranslated regions (3’-UTR) in the mRNA of LYPD3. Consequently, this interaction accelerates the metastasis of HNSCC. Notably, clinical observations indicate a correlation between high expression of miR-151-5p and low levels of LYPD3 in clinical settings are correlated with poor prognosis of HNSCC patients. Furthermore, our investigation demonstrates that glycosylation of LYPD3 modulates its subcellular localization and reinforces its role in suppressing HNSCC metastasis. Additionally, we uncover a potential regulatory mechanism involving the facilitation of miR-151-5p maturation and accumulation through N6-methyladenosine (m6A) modification. This process is orchestrated by methyltransferase-like 3 (METTL3) and mediated by a newly identified reader, heterogeneous nuclear ribonucleoprotein U (hnRNP U). These findings collectively underscore the significance of the METTL3/miR-151-5p/LYPD3 axis serves as a prominent driver in the malignant progression of HNSCC.

Abstract Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic mutations. However, recent studies have revealed the significant role of epigenetic alterations in the progression of colorectal cancer. Epithelial–mesenchymal transition, a critical step in cancer cell metastasis, has been found to be closely associated with the tumor microenvironment and immune factors, thereby playing a crucial role in many kinds of biological behaviors of cancers. In this review, we explored the impact of N6-methyladenosine and post-translational modifications (like methylation, acetylation, ubiquitination, SUMOylation, glycosylation, etc.) on the process of epithelial–mesenchymal transition in colorectal cancer and the epigenetic regulation for the transcription factors and pathways correlated to epithelial-mesenchymal transition. Furthermore, we emphasized that the complex regulation of epithelial-mesenchymal transition by epigenetics can provide new strategies for overcoming drug resistance and improving treatment outcomes. This review aims to provide important scientific evidence for the prevention and treatment of colorectal cancer based on epigenetic modifications.

Abstract Background Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI. Graphical Abstract

The epitranscriptomic mark N6-methyladenosine (m6A) is the most common type of messenger RNA (mRNA) post-transcriptional modification in eukaryotes. With the discovery of the demethylase FTO (FAT MASS AND OBESITYASSOCIATED PROTEIN) in Homo Sapiens, this modification has been proven to be dynamically reversible. With technological advances, research on m6A modification in plants also rapidly developed. m6A modification is widely distributed in plants, which is usually enriched near the stop codons and 3'-UTRs, and has conserved modification sequences. The related proteins of m6A modification mainly consist of three components: methyltransferases (writers), demethylases (erasers), and reading proteins (readers). m6A modification mainly regulates the growth and development of plants by modulating the RNA metabolic processes and playing an important role in their responses to environmental signals. In this review, we briefly outline the development of m6A modification detection techniques; comparatively analyze the distribution characteristics of m6A in plants; summarize the methyltransferases, demethylases, and binding proteins related to m6A; elaborate on how m6A modification functions in plant growth, development, and response to environmental signals; and provide a summary and outlook on the research of m6A in plants. [ABSTRACT FROM AUTHOR]

miRNA has emerged as a crucial regulator in various of pathological and physiological processes, yet its precise mechanism of action the detailed mechanism of their action in Head and neck squamous cell carcinoma (HNSCC) remains incompletely understood. This study sheds light on the role of mi-151-5p, revealing its significantly elevated expression in tumor cells, which notably enhances the invasion and migration of HNSCC cells. This effect is achieved through directly targeting LY6/PLAUR Domain Containing 3 (LYPD3) by miR-151-5p, involving complementary binding to the 3'-untranslated regions (3'-UTR) in the mRNA of LYPD3. Consequently, this interaction accelerates the metastasis of HNSCC. Notably, clinical observations indicate a correlation between high expression of miR-151-5p and low levels of LYPD3 in clinical settings are correlated with poor prognosis of HNSCC patients. Furthermore, our investigation demonstrates that glycosylation of LYPD3 modulates its subcellular localization and reinforces its role in suppressing HNSCC metastasis. Additionally, we uncover a potential regulatory mechanism involving the facilitation of miR-151-5p maturation and accumulation through N6-methyladenosine (m6A) modification. This process is orchestrated by methyltransferase-like 3 (METTL3) and mediated by a newly identified reader, heterogeneous nuclear ribonucleoprotein U (hnRNP U). These findings collectively underscore the significance of the METTL3/miR-151-5p/LYPD3 axis serves as a prominent driver in the malignant progression of HNSCC. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) methylation, as a new regulatory mechanism, has been reported to be involved in diverse biological processes in recent years. Wilms tumor 1-associated protein (WTAP), as the key member of m6A methylation, has been proven to participate in tumorigenesis. Here, we studied the expression of WTAP and its potential mechanism involved in the development of esophageal squamous cell carcinoma (ESCC). We detected the expression of WTAP and its correlation with clinicopathological features, and we determined the function of WTAP on ESCC cells by MTS assay, colony formation, scratch wound healing assay, Transwell assay, and subcutaneous xenografi assay. We used mRNA sequencing technology to screen candidate downstream targets for WTAP and investigated the underlying mechanism of CCND1 in ESCC promotion through a series of rescue assays. An elevated expression of WTAP in ESCC malignancy indicated a worse prognosis. WTAP promoted the proliferation and metastasis of ESCC cells, and CCND1 was identified as the potential downstream effecter of WTAP. Moreover, WTAP modulated ESCC progression through a MAPK pathway-dependent pattern. Our research suggested that WTAP promoted both proliferation and metastasis of ESCC by accelerating the expression of CCND1 via the MAPK signaling pathway, indicating that WTAP may be a candidate prognostic biomarker for ESCC and also will be a promising strategy for ESCC cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. Methods: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated β-gal (SA-β-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. Results: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. Conclusion: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) damage is closely related to skin photoaging and many skin diseases, including dermatic tumors. N6-methyladenosine (m6A) modification is an important epigenetic regulatory mechanism. However, the role of m6A methylation in apoptosis induced by repeated UV irradiation has not been characterized. To explore m6A methylation changes and regulatory mechanisms in the repeated UV-induced skin damage process, especially apoptosis. HaCaT cells and BALB/c-Nu nude mice were exposed to repeated UVB/UVA+UVB irradiation. Colorimetry and flow cytometry were used to measure cellular viability and apoptosis. m6A-modified genes were detected via colorimetry and methylated RNA immunoprecipitation (MeRIP) sequencing. Methyltransferases and demethylases were detected via RT-PCR, western blotting and immunohistochemistry. Transfection of siRNA and plasmid was performed to knock down or overexpress the selected genes. After UVB irradiation, 861 m6A peaks were increased and 425 m6A peaks were decreased in HaCaT cells. The differentially modified genes were enriched in apoptosis-related pathways. The m6A demethylase FTO was decreased in both HaCaT cells and mouse skin after UV damage. Overexpressing FTO could improve cell viability, inhibit apoptosis and decrease RNA-m6A methylation, including LPCAT3-m6A, which increase LPCAT3 expression, cell viability promotion and apoptosis inhibition. Our study identified the cell m6A methylation change lists after repeated UVB irradiation, and revealed that FTO and LPCAT3 play key roles in the m6A methylation pathogenesis of UV-induced skin cell apoptosis. FTO-m6A-LPCAT3 might serve as a novel upstream target for preventing and treating photoaging and UV-induced skin diseases. • FTO-mediated RNA methylation was involved in skin UV damage. • FTO is involved in skin UV damage by regulating cell viability and apoptosis. • m6A modification of LPCAT3 was involved in this process. [ABSTRACT FROM AUTHOR]

In recent years, breast cancer (BC) has surpassed lung cancer as the most common malignant tumor worldwide and remains the leading cause of cancer death in women. The etiology of BC usually involves dysregulation of epigenetic mechanisms and aberrant expression of certain non‐coding RNAs (ncRNAs). N6‐methyladenosine (m6A), the most prevalent RNA modification in eukaryotes, widely exists in ncRNAs to affect its biosynthesis and function, and is an important regulator of tumor‐related signaling pathways. Interestingly, ncRNAs can also regulate or target m6A modification, playing a key role in cancer progression. However, the m6A‐ncRNAs regulatory network in BC has not been fully elucidated, especially the regulation of m6A modification by ncRNAs. Therefore, in this review, we comprehensively summarize the interaction mechanisms and biological significance of m6A modifications and ncRNAs in BC. Meanwhile, we also focused on the clinical application value of m6A modification in BC diagnosis and prognosis, intending to explore new biomarkers and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression. [ABSTRACT FROM AUTHOR]

BACKGROUND: As a critical m6A RNA methylation regulator, HNRNPC has been revealed to serve as potential biomarkers in various human cancers. The specific expression and significance of HNRNPC in colorectal cancer remain unknown. OBJECTIVE: This study aimed to confirm HNRNPC expression level and evaluate its function in colorectal cancer progression. METHODS: 101 paired tissue samples were collected from colorectal cancer patients. HNRNPC levels in colorectal cancer were detected using PCR. CCK8 and transwell assays were conducted to estimate the effect of HNRNPC on cell growth and metastasis with the regulation of HNRNPC by cell transfection. RESULTS: Upregulated HNRNPC was observed in colorectal cancer compared with normal tissues and cells. The higher HNRNPC levels in tumor tissues were associated with the advanced TNM stage and positive lymph node metastasis. Meanwhile, HNRNPC upregulation could indicate adverse outcomes of colorectal cancer patients. In vitro, the knockdown of HNRNPC significantly suppressed the proliferation, migration, and invasion of colorectal cancer cells. CONCLUSIONS: Upregulated HNRNPC served as a biomarker for the prognosis and development of colorectal cancer, which provides a novel therapeutic target for colorectal cancer. [ABSTRACT FROM AUTHOR]

Invasion and migration are the primary factors for mortality in lung adenocarcinoma (LUAD) patients. The precise role of RNA-binding motif protein15 (RBM15)-mediated m6A modification in LUAD is not yet fully clarified. This research aims to elucidate the mechanism of RBM15 in the invasion and migration of LUAD.Western blot and dot blot assay results showed that RBM15 and methylation levels of m6A were highly expressed in LUAD tissues. Overexpression of RBM15 by lentivirus transfection increased m6A levels and promoted the invasion, migration, and proliferation of A549 and H1734 cells. Knockdown of RBM15 by lentivirus transfection had opposite effects on m6A levels, invasion, migration, and proliferation of A549 and H1734 cells. The results of nude mouse proliferation models confirmed that RBM15 knockdown inhibited in vivo tumor proliferation . Sequencing and immunoprecipitation identified RASSF8 as an interacting protein of RBM15 involved in cell invasion and migration. RBM15-mediated m6A modification inhibited RASSF8 protein levels and increased LUAD cell invasion and migration. The rescue assays demonstrated that the regulation of RBM15 on LUAD cell invasion and migration was partially rescued by RASSF8.In conclusion, RBM15-mediated m6A modification inhibits the RASSF8 protein levels and increases cell invasion and migration. Thus, targeting the RBM15-m6A-RASSF8 axis may be a promising strategy for repressing LUAD cell invasion and migration.

Abstract Background N6‐methyladenosine (m6A) has been identified as the most abundant modification of RNA molecules and the aberrant m6A modifications have been associated with the development of autoimmune diseases. However, the role of m6A modification in ankylosing spondylitis (AS) has not been adequately investigated. Therefore, we aimed to explore the significance of m6A regulator‐mediated RNA methylation in AS. Methods The methylated RNA immunoprecipitation sequencing (meRIP‐seq) and digital RNA sequencing (Digital RNA‐seq) were conducted using the peripheral blood mononuclear cells from three AS cases and three healthy controls, to identify genes affected by abnormal RNA methylation. The genes associated with different peaks were cross‐referenced with AS‐related genes obtained from the GeneCards Suite. Subsequently, the expression levels of shared differentially expressed genes (DEGs) and key m6A regulators in AS were evaluated using data from 68 AS cases and 36 healthy controls from two data sets (GSE25101 and GSE73754). In addition, the results were validated through quantitative polymerase chain reaction (qPCR). Results The meRIP‐seq and Digital RNA‐seq analyses identified 28 genes with upregulated m6A peaks but with downregulated expression, and 52 genes with downregulated m6A peaks but with upregulated expression. By intersecting the genes associated with different peaks with 2184 AS‐related genes from the GeneCards Suite, we identified a total of five shared DEGs: BCL11B, KAT6B, IL1R1, TRIB1, and ALDH2. Through analysis of the data sets and qPCR, we found that BCL11B and IL1R1 were differentially expressed in AS. Moreover, two key m6A regulators, WTAP and heterogeneous nuclear ribonucleoprotein C, were identified. Conclusions In conclusion, the current study revealed that m6A modification plays a crucial role in AS and might hence provide a new treatment strategy for AS disease.

Abstract Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Gastric cancer (GC) is one of the most common malignancies in the digestive system. Many patients are found in advanced stage and have a poor prognosis. Surgery and chemotherapy remain the main treatments for gastric cancer. N6-methyladenosine (m6A) is a hot topic in tumor research in recent years. As the most common form of RNA modification in eukaryotes, m6A can regulate various stages of the RNA cycle, including RNA splicing, processing, degradation, and translation, thereby regulating RNA expression and function, playing a critical role in various pathways such as cell differentiation, development, and metabolism. The m6A demethylase can remove methyl groups on RNA, ensuring that m6A methylation is a dynamic and reversible process. As a key enzyme in the m6A methylation process, the imbalance of m6A demethylases fat mass and obesity-associated protein (FTO), AlkB homolog 5 (ALKBH5) and ALKBH3 regulate the progression of gastric cancer through various mechanisms, which is closely related to the occurrence and development of gastric cancer. These m6A demethylases regulate the signaling pathway, alter the proliferation and invasion ability of gastric cancer cells, affect its resistance to chemotherapy drugs, participate in regulating the immune response and mitochondrial metabolism of gastric cancer, and affect the growth of gastric cancer cells. They are expected to become a novel therapeutic target. This article comprehensively summarizes the molecular mechanism of m6A demethylase involved in the occurrence and development of gastric cancer, and the relationship between its expression and function, and biological characteristics of m6A demethylase were reviewed, aiming to provide new research ideas for early diagnosis and targeted treatment of gastric cancer.

N6-methyladenosine (m6A) is a widespread post-transcriptional modification of RNA in eukaryotes. The conserved YTH-domain-containing RNA binding protein has been widely reported to serve as a typical m6A reader in various species. However, no studies have reported the m6A readers in Ginkgo biloba (G. biloba). In this study, a systematic analysis of the m6A reader (YTH) gene family was performed on G. biloba, identifying 10 YTH genes in its genome. Phylogenetic analysis of protein-coding sequences revealed that YTH genes from G. biloba could be classified into two subgroups: GbDC1 and GbDC2 in GbDC and GbDF1-8 in GbDF, each with similar motifs and gene structures. In G. biloba, the predicated aromatic cage pocket of the YTH domains in the YTH gene family is uniformly composed of tryptophan residues (WWW). Subcellular localization experiments verified that GbDC1 is indeed localized in the nucleus, while GbDF1 is localized in both the nucleus and the cytoplasm. The expression patterns of the identified m6A reader genes showed a wide distribution but were tissue-specific. Most genes were highly expressed in leaves, followed by the stem, while the lowest expression tendency was found in the roots. Cis-regulatory element analysis predicted the possible functions of YTH genes in G. biloba, which were mainly responsive to plant hormones such as ABA and MeJA, as well as stress responses. Furthermore, the expression levels of YTH genes indeed changed significantly after ABA, MeJA, and NaCl treatments, suggesting that they can be affected by these abiotic factors. In addition, the PLAAC prediction results indicate that prion domains exist in GbDF1, GbDF2, GbDF3, GbDF4, GbDF6, GbDF7, GbDF8, and GbDC1, and phase separation is possible. This study provides a foundation for further investigation of the effects of m6A methylation on gene expression regulation in G. biloba and other forest trees.