bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2023–08–13
nineteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases.
  2. Molecular Mechanism of m6A Methylation Modification Genes METTL3 and FTO in Regulating Heat Stress in Sheep.
  3. Comprehensive analysis of m6A regulators and relationship with tumor microenvironment, immunotherapy strategies in colorectal adenocarcinoma.
  4. N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential.
  5. Targeted mRNA demethylation in Arabidopsis using plant m6A editor.
  6. Role of TNF-α-induced m6A RNA methylation in diseases: a comprehensive review.
  7. N6-methyladenosine (m6A) methyltransferase WTAP-mediated miR-92b-5p accelerates osteoarthritis progression.
  8. METTL3-mediated N6-methyladenosine modification stimulates mitochondrial damage and ferroptosis of kidney tubular epithelial cells following acute kidney injury by modulating the stabilization of MDM2-p53-LMNB1 axis.
  9. The crucial roles of m6A RNA modifications in cutaneous cancers: Implications in pathogenesis, metastasis, drug resistance, and targeted therapies.
  10. Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer's disease.
  11. Decreased expression of the m6A RNA methyltransferase METTL3 is associated with residual ridge resorption.
  12. Genes associated with N6-methyladenosine regulators provide insight into the prognosis and immune response to renal clear cell carcinoma.
  13. The m6A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m6A dependent manner.
  14. YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-reperfusion Injury.
  15. Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome.
  16. CircCDK1 blocking IGF2BP2-mediated m6A modification of CPPED1 promotes laryngeal squamous cell carcinoma metastasis via the PI3K/AKT signal pathway.
  17. m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1.
  18. Reinvestigating the clinical relevance of the m6A writer METTL3 in urothelial carcinoma of the bladder.
  19. Mettl14-mediated m6 A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state.
  1. Genes Dis. 2023 Nov;10(6): 2351-2365
    Studies on the fat mass and obesity-associated (FTO) gene and its impact on obesity-associated diseases.
    Chaoqun Huang, Wei Chen, Xinxia Wang.
      Obesity has become a major health crisis in the past ∼50 years. The fat mass and obesity-associated (FTO) gene, identified by genome-wide association studies (GWAS), was first reported to be positively associated with obesity in humans. Mice with more copies of the FTO gene were observed to be obese, while loss of the gene in mice was found to protect from obesity. Later, FTO was found to encode an m6A RNA demethylase and has a profound effect on many biological and metabolic processes. In this review, we first summarize recent studies that demonstrate the critical roles and regulatory mechanisms of FTO in obesity and metabolic disease. Second, we discuss the ongoing debates concerning the association between FTO polymorphisms and obesity. Third, since several small molecule drugs and micronutrients have been found to regulate metabolic homeostasis through controlling the expression or activity of FTO, we highlight the broad potential of targeting FTO for obesity treatment. Improving our understanding of FTO and the underlying mechanisms may provide new approaches for treating obesity and metabolic diseases.
    Keywords:  Adipogenesis; FTO; Metabolic diseases; N6-methyladenosine; Obesity; RNA m6A modification
    DOI:  https://doi.org/10.1016/j.gendis.2022.04.014
  2. Int J Mol Sci. 2023 Jul 25. pii: 11926. [Epub ahead of print]24(15):
    Molecular Mechanism of m6A Methylation Modification Genes METTL3 and FTO in Regulating Heat Stress in Sheep.
    Bowen Chen, Chao Yuan, Tingting Guo, Jianbin Liu, Bohui Yang, Zengkui Lu.
      Heat stress is an important environmental factor affecting livestock production worldwide. Primary hepatocytes and preadipocytes derived from Hu sheep were used to establish a heat stress model. Quantitative reverse transcriptase-PCR (qRT-PCR) analysis showed that heat induction significantly increased the expression levels of heat stress protein (HSP) genes and the N6-methyladenosine (m6A) methylation modification genes: methyltransferase-like protein 3 (METTL3), methyltransferase-like protein 14 (METTL14), and fat mass and obesity associated protein (FTO). Heat stress simultaneously promoted cell apoptosis. Transcriptome sequencing identified 3980 upregulated genes and 2420 downregulated genes related to heat stress. A pathway enrichment analysis of these genes revealed significant enrichment in fatty acid biosynthesis, degradation, and the PI3K-Akt and peroxisome proliferator-activated receptor (PPAR) signaling pathways. Overexpression of METTL3 in primary hepatocytes led to significant downregulation of HSP60, HSP70, and HSP110, and significantly increased mRNA m6A methylation; FTO interference generated the opposite results. Primary adipocytes showed similar results. Transcriptome analysis of cells under METTL3 (or FTO) inference and overexpression revealed differentially expressed genes enriched in the mitogen-activated protein kinase (MAPK) signaling pathways, as well as the PI3K-Akt and Ras signaling pathways. We speculate that METTL3 may increase the level of m6A methylation to inhibit fat deposition and/or inhibit the expression of HSP genes to enhance the body's resistance to heat stress, while the FTO gene generated the opposite molecular mechanism. This study provides a scientific basis and theoretical support for sheep feeding and management practices during heat stress.
    Keywords:  FTO; METTL3; heat stress; m6A methylation; sheep
    DOI:  https://doi.org/10.3390/ijms241511926
  3. BMC Genom Data. 2023 Aug 11. 24(1): 44
    Comprehensive analysis of m6A regulators and relationship with tumor microenvironment, immunotherapy strategies in colorectal adenocarcinoma.
    Jian Ji, Shichao Liu, Yongyuan Liang, Guixi Zheng.
       BACKGROUND: The N6-methyladenosine (m6A) RNA modification is the most prevalent and abundant type found in eukaryotic cells. It plays a crucial role in the initiation and progression of cancers. In this study, we aimed to comprehensively investigate the landscape of m6A regulators and their association with tumor microenvironment (TME), immunotherapeutic strategies in colon adenocarcinoma (COAD).
    RESULTS: The differential expression, mutation, CNV frequency and prognostic value of 27 m6A regulators were systematically analyzed in COAD. Patients were classified into two clusters based on m6A regulators through consistent clustering analysis, with cluster A showing significant survival benefits. Most of the m6A regulators were negatively correlated with immune cells, except for WTAP, IGF2BP3, FTO, ALKBH5, which showed a positive correlation. We developed an m6A scoring system to calculate the m6Ascore for each patient. Patients with a high-m6Ascore had a better outcome, with the AUC of 0.775. An independent cohort of 416 COAD patients acquired from GSE38832 database was used to validate the prognosis prediction ability of m6Ascore. Moreover, the m6Ascore was negatively correlated with infiltration of anti-tumor immune cells. Additionally, patients with a high-m6Ascore responded better to anti-PD1 and anti-CTLA4 therapies, and those with MSI-H had a higher m6Ascore. Finally, we investigated the value of m6Ascore in predicting the response of patients to 15 commonly used drugs.
    CONCLUSIONS: We comprehensively analyzed m6A regulators in COAD, including RNA expression, CNV changes, mutations and their correlation with TME. Our results showed that the m6A scoring system had significant predictive power for the prognosis of COAD patients, potentially leading to new personalized immunotherapy strategies.
    Keywords:  Colon adenocarcinoma; Immunotherapy; N6-methyladenosine; Prognosis; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12863-023-01149-y
  4. Biochim Biophys Acta Gene Regul Mech. 2023 Aug 06. pii: S1874-9399(23)00062-7. [Epub ahead of print] 194967
    N6-methyladenosine (m6A) methylation in kidney diseases: Mechanisms and therapeutic potential.
    Yuting Sun, De Jin, Ziwei Zhang, Hangyu Ji, Xuedong An, Yuehong Zhang, Cunqing Yang, Wenjie Sun, Yuqing Zhang, Yingying Duan, Xiaomin Kang, Linlin Jiang, Xuefei Zhao, Fengmei Lian.
      The N6-methyladenosine (m6A) modification is regulated by methylases, commonly referred to as "writers," and demethylases, known as "erasers," leading to a dynamic and reversible process. Changes in m6A levels have been implicated in a wide range of cellular processes, including nuclear RNA export, mRNA metabolism, protein translation, and RNA splicing, establishing a strong correlation with various diseases. Both physiologically and pathologically, m6A methylation plays a critical role in the initiation and progression of kidney disease. The methylation of m6A may also facilitate the early diagnosis and treatment of kidney diseases, according to accumulating research. This review aims to provide a comprehensive overview of the potential role and mechanism of m6A methylation in kidney diseases, as well as its potential application in the treatment of such diseases. There will be a thorough examination of m6A methylation mechanisms, paying particular attention to the interplay between m6A writers, m6A erasers, and m6A readers. Furthermore, this paper will elucidate the interplay between various kidney diseases and m6A methylation, summarize the expression patterns of m6A in pathological kidney tissues, and discuss the potential therapeutic benefits of targeting m6A in the context of kidney diseases.
    Keywords:  Kidney diseases; Mechanistic interpretation; N6-methyladenosine; Targeted therapy; m6A methylation
    DOI:  https://doi.org/10.1016/j.bbagrm.2023.194967
  5. Plant Methods. 2023 Aug 09. 19(1): 81
    Targeted mRNA demethylation in Arabidopsis using plant m6A editor.
    Ruiqiu Fang, Xiaolong Chen, Jie Shen, Bin Wang.
       BACKGROUND: N6-methyladenosine (m6A) is an important epigenetic modification involved in RNA stability and translation regulation. Manipulating the expression of RNA m6A methyltransferases or demethylases makes it difficult to study the effect of specific RNA methylation.
    RESULTS: In this study, we report the development of Plant m6A Editors (PMEs) using dLwaCas13a (from L. wadei) and human m6A demethylase ALKBH5 catalytic domain. PMEs specifically demethylates m6A of targeted mRNAs (WUS, STM, FT, SPL3 and SPL9) to increase mRNAs stability. In addition, we discovered that a double ribozyme system can significantly improve the efficiency of RNA editing.
    CONCLUSION: PMEs specifically demethylates m6A of targeted mRNAs to increase mRNAs stability, suggesting that this engineered tool is instrumental for biotechnological applications.
    Keywords:  ALKBH5; Arabidopsis; N6-methyladenosine; Plant m6A editors; dLwaCas13a
    DOI:  https://doi.org/10.1186/s13007-023-01053-7
  6. Front Cell Dev Biol. 2023 ;11 1166308
    Role of TNF-α-induced m6A RNA methylation in diseases: a comprehensive review.
    Youlin Wang, Jing Liu, Yongchen Wang.
      Tumor Necrosis Factor-alpha (TNF-α) is ubiquitous in the human body and plays a significant role in various physiological and pathological processes. However, TNF-α-induced diseases remain poorly understood with limited efficacy due to the intricate nature of their mechanisms. N6-methyladenosine (m6A) methylation, a prevalent type of epigenetic modification of mRNA, primarily occurs at the post-transcriptional level and is involved in intranuclear and extranuclear mRNA metabolism. Evidence suggests that m6A methylation participates in TNF-α-induced diseases and signaling pathways associated with TNF-α. This review summarizes the involvement of TNF-α and m6A methylation regulators in various diseases, investigates the impact of m6A methylation on TNF-α-induced diseases, and puts forth potential therapeutic targets for treating TNF-α-induced diseases.
    Keywords:  N6-methyladenosine (m6A); TNF-α; autoimmune disease; immunity; signaling pathway
    DOI:  https://doi.org/10.3389/fcell.2023.1166308
  7. Cell Commun Signal. 2023 Aug 10. 21(1): 199
    N6-methyladenosine (m6A) methyltransferase WTAP-mediated miR-92b-5p accelerates osteoarthritis progression.
    Zhaowei Lin, Tao Jiang, Wei Zheng, Jiayuan Zhang, Anan Li, Chao Lu, Wengang Liu.
      The study was design to investigate the functional roles of Wilms tumor 1-associated protein (WTAP), an enzyme catalyzes m6A modification, in the pathogenesis of osteoarthritis (OA) and further elucidate its possible regulatory mechanism. Herein, we discovered that WTAP was outstandingly upregulated in chondrocyte stimulated with Lipopolysaccharide (LPS) and cartilage tissue of patients with OA. Functional studies have demonstrated that WTAP knockdown enhances proliferation ability, suppresses apoptosis, and reduces extracellular matrix (ECM) degradation in an LPS-induced OA chondrocyte injury model and ameliorates cartilage damage in a destabilizing the medial meniscus (DMM)-induced OA mice model. Conversely, overexpression of WTAP contributes to the opposite effects. Mechanistically, our data has demonstrated that m6A modification mediated by WTAP promotes the maturation of pri-miR-92b to miR-92b-5p, thereby enhancing the targeted inhibitory function of miR-92b-5p on TIMP4. Furthermore, we have discovered that WTAP can directly facilitate the degradation of TIMP4 mRNAs in a YTHDF2-dependent manner. In a nutshell, our findings suggested that WTAP knockdown alleviated OA progression by modulating the miR-92b-5p/TIMP4 axis in an m6A-dependent manner. Our study disclosed that WTAP-mediated m6A modification displayed a crucial role in OA development and suggested that targeting WTAP could be a promising preventive and therapeutic target for patients with OA. Video Abstract.
    DOI:  https://doi.org/10.1186/s12964-023-01228-8
  8. Eur J Med Chem. 2023 Jul 23. pii: S0223-5234(23)00643-8. [Epub ahead of print]259 115677
    METTL3-mediated N6-methyladenosine modification stimulates mitochondrial damage and ferroptosis of kidney tubular epithelial cells following acute kidney injury by modulating the stabilization of MDM2-p53-LMNB1 axis.
    Chenghuan Hu, Buyao Zhang, Shuangping Zhao.
      N6-methyladenosine (m6A) and MELLT3 assume a role in the development of acute kidney injury (AKI). However, their mechanism in AKI remains under-explored. On this basis, this study explored the mechanism of MELLT3 in mitochondrial damage and ferroptosis of kidney tubular epithelial cells after AKI. HK-2 cells were induced by lipopolysaccharide (LPS) to simulate AKI, followed by gain and loss of function of genes, detection of mitochondrial damage and ferroptosis indicators, and analysis of gene interactions. An AKI mouse model was developed using the cecal ligation and puncture (CLP) method to investigate the effect of METTL3 knockdown on kidney injury. MDM2 and LMNB1 were upregulated and p53 was downregulated in LPS-treated HK-2 cells. Mechanistically, the E3 ubiquitin ligase MDM2 increased p53 ubiquitination to activate LMNB1. METTL3 knockdown decreased m6A methylation of MDM2, thus diminishing YTHDF1-mediated MDM2 mRNA stability and translation in LPS-treated HK-2 cells. Knockdown of LMNB1, MDM2, or METTL3 reduced NO, MDA, iron ion, and ROS levels as well as mitochondrial damage and raised SOD, GSH, XCT, GPX4, FPN1, and TFR1 levels in LPS-treated HK-2 cells. The in vivo results showed that METTL3 knockdown reduced renal injury and ferroptosis in CLP mice. METTL3 knockdown prevents mitochondrial damage and ferroptosis of kidney tubular epithelial cells after AKI via the MDM2-p53-LMNB1 axis.
    Keywords:  Acute kidney injury; Ferroptosis; LMNB1; MDM2; METTL3; Mitochondrial damage; Ubiquitination; m(6)A methylation; p53
    DOI:  https://doi.org/10.1016/j.ejmech.2023.115677
  9. Genes Dis. 2023 Nov;10(6): 2320-2330
    The crucial roles of m6A RNA modifications in cutaneous cancers: Implications in pathogenesis, metastasis, drug resistance, and targeted therapies.
    Cong Huang, Kaoyuan Zhang, Yang Guo, Changbing Shen, Xiaoming Liu, Haiyan Huang, Xia Dou, Bo Yu.
      N6-methyladenosine (m6A) is the most abundant internal modification on RNA. It is a dynamical and reversible process, which is regulated by m6A methyltransferase and m6A demethylase. The m6A modified RNA can be specifically recognized by the m6A reader, leading to RNA splicing, maturation, degradation or translation. The abnormality of m6A RNA modification is closely related to a variety of biological processes, especially the occurrence and development of tumors. Recent studies have shown that m6A RNA modification is involved in the pathogenesis of skin cancers. However, the precise molecular mechanisms of m6A-mediated cutaneous tumorigenesis have not been fully elucidated. Therefore, this review will summarize the biological characteristics of m6A modification, its regulatory role and mechanism in skin cancers, and the recent research progress of m6A-related molecular drugs, aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.
    Keywords:  Cutaneous melanoma; Cutaneous squamous cell carcinoma; Target Therapy; m6A modification; m6A-related drugs
    DOI:  https://doi.org/10.1016/j.gendis.2022.03.006
  10. PLoS One. 2023 ;18(8): e0289068
    Influence of N6-methyladenosine (m6A) modification on cell phenotype in Alzheimer's disease.
    Pengyun Ni, Kaiting Pan, Bingbing Zhao.
       OBJECTIVE: Recent research has suggested that m6A modification takes on critical significance to Neurodegeneration. As indicated by the genome-wide map of m6A mRNA, genes in Alzheimer's disease model achieved significant m6A methylation. This study aimed to investigate the hub gene and pathway of m6A modification in the pathogenesis of AD. Moreover, possible brain regions with higher gene expression levels and compounds exerting potential therapeutic effects were identified. Thus, this study can provide a novel idea to explore the treatment of AD.
    METHODS: Differential expression genes (DEGs) of GSE5281 and GSE48350 from the Gene Expression Omnibus (GEO) database were screened using the Limma package. Next, the enrichment analysis was conducted on the screened DEGs. Moreover, the functional annotation was given for N6-methyladenosine (m6A) modification gene. The protein-protein interaction network (PPI) analysis and the visualization analysis were conducted using STRING and Cytoscape. The hub gene was identified using CytoHubba. The expression levels of Hub genes in different regions of brain tissue were analyzed based on Human Protein Atlas (HPA) database and Bgee database. Subsequently, the candidate drugs targeting hub genes were screened using cMAP.
    RESULTS: A total of 42 m6A modified genes were identified in AD (20 up-regulated and 22 down-regulated genes). The above-described genes played a certain role in biological processes (e.g., retinoic acid, DNA damage response and cysteine-type endopeptidase activity), cellular components (e.g., mitochondrial protein complex), and molecular functions (e.g., RNA methyltransferase activity and ubiquitin protein ligase). KEGG results suggested that the above-mentioned genes were primarily involved in the Hippo signaling pathway of neurodegeneration disease. A total of 10 hub genes were screened using the protein-protein interaction network, and the expression of hub genes in different regions of human brain was studied. Furthermore, 10 compounds with potential therapeutic effects on AD were predicted.
    CONCLUSION: This study revealed the potential role of the m6A modification gene in Alzheimer's disease through the bioinformatics analysis. The biological changes may be correlated with retinoic acid, DNA damage response and cysteine-type endopeptidase activity, which may occur through Hippo signaling pathway. The hub genes (SOX2, KLF4, ITGB4, CD44, MSX1, YAP1, AQP1, EGR2, YWHAZ and TFAP2C) and potential drugs may provide novel research directions for future prognosis and precise treatment.
    DOI:  https://doi.org/10.1371/journal.pone.0289068
  11. J Oral Biol Craniofac Res. 2023 Sep-Oct;13(5):13(5): 563-566
    Decreased expression of the m6A RNA methyltransferase METTL3 is associated with residual ridge resorption.
    Harini Sri Krishnamoorthy, Balachander Kannan, Dhanraj Ganapathy, Vijayashree Priyadharsini Jayaseelan, Paramasivam Arumugam.
       Objective: N6-methyladenosine (m6A) methylation and its regulators play crucial roles in the progression of osteoporosis (OP) by regulating the expression of osteoporosis-related genes. In this study, we have analyzed the expression of methyltransferase-like 3 (METTL3) and its target gene Runt-related transcription factor 2 (RUNX2) in patients with residual ridge resorption (RRR).
    Materials and methods: A total 50 number of participants were included in this comparative study (RRR - n25 and healthy control - n25). Total RNA was extracted from peripheral blood and converted into cDNA. METTL3 and RUNX2 expression levels were quantified using RT-qPCR with GAPDH as the reference gene. Bioinformatics tools were used to identify gene functions and pathways.
    Results: Real-time polymerase chain reaction (qPCR) revealed that METTL3 and RUNX2 expression was downregulated in the RRR group compared to that in healthy controls (P < 0.05). In silico functional analysis provided information regarding the role of METTL3 in various biological processes.
    Conclusion: Our findings suggest that METTL3 dysregulation contributes to RRR pathogenesis. Further large-scale samples and functional studies are required to identify their therapeutic potential.
    Keywords:  Genetics; Health; METTL3; Residual ridge resorption; m6A methylation
    DOI:  https://doi.org/10.1016/j.jobcr.2023.07.003
  12. Environ Toxicol. 2023 Aug 09.
    Genes associated with N6-methyladenosine regulators provide insight into the prognosis and immune response to renal clear cell carcinoma.
    Guobin Fan, Dejun Wu, Huaping Chen, Zhi Wen, Linhui Liao, Shuming He, Jie Yang.
      As one of the most common messenger ribonucleic acid modifications in eukaryotic organisms, N6-methyladenosine (m6A) is involved in a wide variety of biological functions. The imbalance of m6A RNA modification may be linked to cancer and other disorders, according to a growing body of studies. Its effects on clear cell renal cell carcinoma (KIRC) have not been well discussed, though. Here, we acquired the expression patterns of 23 important regulators of m6A RNA modification and assess how they might fare in KIRC. We observed that 17 major m6A RNA modification regulatory factors had a substantial predictive influence on KIRC. Using the "ConsensusCluster" program, we defined two groupings (Cluster 1 and Cluster 2) depending on the expression of the aforementioned 17 key m6A RNA methylation regulators. The Cluster 2 has a less favorable outcome and is strongly related with a lesser immune microenvironment, according to the findings. We also developed a strong risk profile for three m6A RNA modifiers (METTL14, YTHDF1, and LRPPRC) using multivariate Cox regression analysis. According to further research, the aforementioned risk profile could serve as an independent predicting factor for KIRC, and the chemotherapy response sensitivity was analyzed between two risk groups. Moreover, to effectively forecast the future outlook of KIRC clients, we established a novel prognostic approach according to gender, age, histopathological level, clinical stage, and risk score. Finally, the function of hub gene METTL14 was validated by cell proliferation and subcutaneous graft tumor in mice. In conclusion, we discovered that m6A RNA modifiers play an important role in controlling KIRC and created a viable risk profile as a marker of prediction for KIRC clients.
    Keywords:  N6-methyladenosine (m6A); cox regression; kidney renal clear cell carcinoma (KIRC); prognosis model
    DOI:  https://doi.org/10.1002/tox.23920
  13. Int J Biol Sci. 2023 ;19(12): 3987-4003
    The m6A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m6A dependent manner.
    Meng-Yun Ke, Yi Fang, Hui Cai, Jian-Wen Lu, Lin Yang, Yue Wang, Rong-Qian Wu, Xu-Feng Zhang, Yi Lv, Jian Dong.
      Background and Aims: N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various biological processes. However, its roles in fulminant hepatitis remain largely unknown. In the current study, YTHDF1 expression was found to be significantly downregulated in the livers among patients, as well as murine models with fulminant hepatitis versus normal controls. Thus, we hypothesized that YTHDF1 protects against fulminant hepatitis and investigated the underlying molecular mechanisms. Methods: Fulminant hepatitis was induced by D-GalN/LPS in conventional YTHDF1 knockout (YTHDF1-/-) mice, hepatocyte-specific YTHDF1 overexpression (AAV8- YTHDF1) mice, and corresponding control mice. Primary hepatocytes were cultured and subjected to LPS insult in vitro. Hepatic histology, cell death, oxidative stress and mitochondrial function were examined to assess liver damage. The molecular mechanisms of YTHDF1 function were explored using multi-omics analysis. Results: Ablation of YTHDF1 exacerbated hepatic apoptosis and reactive oxygen species (ROS) production and increased the number of aberrant mitochondria, while YTHDF1 overexpression resulted in the opposite effects. Multiomics analysis identified MFG-E8 as the direct target of YTHDF1. YTHDF1 augmented the translation of MFG-E8 in an m6A-dependent manner without effect on its mRNA expression, thereby restoring mitochondrial function. Additionally, administration of MFG-E8 almost completely reversed the YTHDF1 deficiency-mediated exacerbation of liver injury. Conclusions: The current study suggested that the m6A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m6A-dependent manner.
    Keywords:  Acute liver failure; MFG-E8; Mitochondria; YTHDF1; m6A
    DOI:  https://doi.org/10.7150/ijbs.84768
  14. Antioxid Redox Signal. 2023 Aug 07.
    YTHDF2 Promotes Cardiac Ferroptosis via Degradation of SLC7A11 in Cardiac Ischemia-reperfusion Injury.
    Ping Pang, Wei Si, Han Wu, Jiaming Ju, Kuiwu Liu, Chunlei Wang, Yingqiong Jia, Hongtao Diao, Linghua Zeng, Weitao Jiang, Yang Yang, Yuting Xiong, Xue Kong, Zhengwei Zhang, Feng Zhang, Jinglun Song, Yu Bian, Ning Wang, Baofeng Yang.
       AIMS: Myocardial ischemia-reperfusion (I/R) injury facilitates cardiomyocyte death and endangers human health. N6-methyladenosine (m6A) methylation plays a critical role in cardiovascular diseases. The m6A reader YTHDF2 identifies m6A-modified RNA and promotes target RNA degradation. Hence, we hypothesized that YTHDF2 affects I/R injury by regulating RNA stability.
    RESULTS: Both mRNA and protein levels of YTHDF2 were upregulated in I/R mice and hypoxia-reoxygenation (H/R)-induced cardiomyocytes. Silencing of endogenous YTHDF2 abrogated cardiac dysfunction and lowered the infarct size in I/R mice, and forced expression of YTHDF2 aggravated these adverse pathological processes. Consistently, the protective effect of silencing YTHDF2 occurred in cardiomyocytes exposed to H/R and erastin. Furthermore, RNA-seq and RIP revealed that YTHDF2 recognized the m6A modification sites of the ferroptosis-related gene SLC7A11 mRNA to promote its degradation both in vivo and in vitro. Inhibition of SLC7A11 impaired cardiac function, increased infarct size, and the release of LDH in I/R mice after silencing YTHDF2. The beneficial effects of si-YTHDF2 on H/R injury were reversed by co-transfection with si-SLC7A11, which substantially exacerbated ferroptosis and the production of ROS.
    INNOVATION AND CONCLUSION: The cardioprotective effects of silencing YTHDF2 are accomplished by increasing SLC7A11 stability and expression and reducing ferroptosis, providing novel potential therapeutic targets for treating ischemic cardiac diseases.
    DOI:  https://doi.org/10.1089/ars.2023.0291
  15. J Ovarian Res. 2023 Aug 08. 16(1): 157
    Alteration of the N6-methyladenosine methylation landscape in a mouse model of polycystic ovary syndrome.
    Lingxiao Zou, Waixing Li, Dabao Xu, Shujuan Zhu, Bin Jiang.
       OBJECTIVE: To explore the N6-methyladenosine (m6A) methylation abnormality of mRNAs and its potential roles in the mouse model of polycystic ovary syndrome (PCOS).
    METHODS: The mouse model of PCOS were induced by injecting dehydroepiandrosterone (DHEA), and confirmed by observing the morphological structures of ovarian follicles. Subsequently, m6A-tagged mRNAs were identified via m6A epitranscriptomic microarray and its potential functional pathways were predicted in KEGG database. The expression and modification levels of key mRNAs in the most enriched pathway were evaluated and compared using western blot and methylated RNA immunoprecipitation-quantitative PCR (MeRIP-qPCR).
    RESULTS: Compared with the control group, 415 hypermethylated and downregulated mRNAs, 8 hypomethylated and upregulated mRNAs, and 14 hypermethylated and upregulated mRNAs were identified in the PCOS group (Fold change ≥ 1.5). Those mRNAs were mainly involved in insulin signaling pathway, type II diabetes mellitus, Fc epsilon RI signaling pathway, inositol phosphate metabolism, and GnRH secretion. In insulin signaling pathway, the expression levels of phosphorylated protein kinase B (p-AKT) were decreased, whereas that of upstream phosphorylated phosphatidylinositol 3-kinase (p-PI3K) were increased in PCOS group. Moreover, skeletal muscle and kidney-enriched inositol polyphosphate 5-phosphatease (SKIP), one of PIP3 phosphatases, was verified to be overexpressed, and Skip mRNAs were hypermethylated in PCOS group.
    CONCLUSION: The altered m6A modification of mRNAs might play a critical role in PCOS process. The PI3K/AKT pathway is inhibited in the mouse model of PCOS. Whether it is caused by the m6A modification of Skip mRNAs is worthy of further exploration.
    Keywords:  Epitranscriptomic microarray; N6-methyladenosine; PI3K/AKT pathway; Polycystic ovary syndrome; mRNA
    DOI:  https://doi.org/10.1186/s13048-023-01246-7
  16. Gene. 2023 Aug 03. pii: S0378-1119(23)00527-9. [Epub ahead of print] 147686
    CircCDK1 blocking IGF2BP2-mediated m6A modification of CPPED1 promotes laryngeal squamous cell carcinoma metastasis via the PI3K/AKT signal pathway.
    Jinling Li, Huan Cao, Jianwang Yang, Baoshan Wang.
       BACKGROUND: Circular RNA (circRNA) is a novel noncoding RNA (ncRNA) that plays a critical role in various cancers. However, the clinical significance, biological function, and molecular mechanisms of circRNAs in laryngeal squamous cell carcinoma (LSCC) remain unclear.
    METHODS: A circRNA array was performed to identify the differentially expressed circRNAs. In vitro and in vivo assays were proceeded to verify the biological function of circCDK1 in LSCC. RNA pulldown assays and RNA immunoprecipitation (RIP) were used to confirm the binding between circCDK1 and insulin-like growth factor 2 mRNA binding protein 2(IGF2BP2). The MeRIP assay was then used to identified the N6-methyladenisine (m6A) methylation of calcineurin like phosphatase domain containing1 (CPPED1).
    RESULTS: Hsa_circ_0005774 (circCDK1) was found upregulated in LSCC tissues compared to adjacent normal tissues. The level of circCDK1 was positively correlated with poor prognosisof LSCC patients. In vitro and in vivo, circCDK1 promoted migration and invasion of LSCC cells. Mechanistically, eukaryotic translation initiation factor4A3(EIF4A3) induced biogenesis of circCDK1 by binding to its flanking. By competitively binding to IGF2BP2, circCDK1 blocked the m6A modification of CPPED1 in IGF2BP2-dependent manner. Moreover, the circCDK1-mediated decrease of CPPED1 activated the PI3K/AKT signal pathway to facilitate progression of LSCC.
    CONCLUSIONS: Our findings demonstrated that EIF4A3-induced upregulation of circCDK1 promoted LSCC metastasis via EIF4A3-circCDK1-IGF2BP2-CPPED1 to activate PI3K-AKT signal pathway. CircCDK1 might serve as a new diagnostic and prognostic marker or potential therapeutic target for LSCC.
    Keywords:  CPPED1; CircCDK1; IGF2BP2; Laryngeal squamous cell carcinoma; Metastasis; N6-methyladenisine methylation
    DOI:  https://doi.org/10.1016/j.gene.2023.147686
  17. Cancer Gene Ther. 2023 Aug 10.
    m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1.
    Changkun Huang, Ran Xu, Xuan Zhu, Hongyi Jiang.
      Prostate cancer (PCa) is a malignant tumor of the urinary system. CircABCC4 has been demonstrated to promote the development of PCa; however, its regulatory mechanisms in PCa progression remain largely unknown. We found that circABCC4 was highly expressed in PCa tissues and cells, and elevated circABCC4 level indicated a poor overall survival of PCa patients. METTL3 overexpression increased circABCC4 expression via m6A modification in PCa cells. Functionally, knockdown of circABCC4 or METTL3 repressed PCa cell stemness, migration, and invasion in vitro and delayed PCa cancer growth and metastasis in vivo. circABCC4 knockdown-mediated inhibition in PCa cell stemness and metastasis could be counteracted by overexpression of wild-type circABCC4 with m6A sites. Mechanistically, circABCC4 recruited IGF2BP2 protein to CCAR1 mRNA, thereby enhancing CCAR1 mRNA stability and subsequent activation of the Wnt/β-catenin pathway. Overexpression of CCAR1 counteracted the inhibitory effect of circABCC4 silencing on PCa cell stemness and metastasis. These results revealed that m6A-modified circABCC4 by METTL3 facilitated PCa cell stemness and metastasis by interacting with IGF2BP2 to increase the stability and expression of CCAR and subsequent expression of Wnt/β-catenin target genes. Our findings suggest circABCC4 as a promising therapeutic target for PCa.
    DOI:  https://doi.org/10.1038/s41417-023-00650-x
  18. iScience. 2023 Aug 18. 26(8): 107300
    Reinvestigating the clinical relevance of the m6A writer METTL3 in urothelial carcinoma of the bladder.
    Jonas Koch, Manuel Neuberger, Martina Schmidt-Dengler, Jinyun Xu, Vitor Coutinho Carneiro, Jörg Ellinger, Maximilian C Kriegmair, Philipp Nuhn, Philipp Erben, Maurice Stephan Michel, Mark Helm, Manuel Rodríguez-Paredes, Malin Nientiedt, Frank Lyko.
      METTL3 is the major writer of N6-Methyladenosine (m6A) and has been associated with controversial roles in cancer. This is best illustrated in urothelial carcinoma of the bladder (UCB), where METTL3 was described to have both oncogenic and tumor-suppressive functions. Here, we reinvestigated the role of METTL3 in UCB. METTL3 knockout reduced the oncogenic phenotype and m6A levels of UCB cell lines. However, complete depletion of METTL3/m6A was not achieved due to selection of cells expressing alternative METTL3 isoforms. Systematic vulnerability and inhibitor response analyses suggested that uroepithelial cells depend on METTL3 for viability. Furthermore, expression and survival analyses of clinical data revealed a complex role for METTL3 in UCB, with decreased m6A mRNA levels in UCB tumors. Our results suggest that METTL3 expression may be a suitable diagnostic UCB biomarker, as the enzyme promotes UCB formation. However, the suitability of the enzyme as a therapeutic target should be evaluated carefully.
    Keywords:  Biological sciences; Cancer systems biology; Epigenetics; Molecular biology; Molecular mechanism of gene regulation; Natural sciences; Oncology; Systems biology
    DOI:  https://doi.org/10.1016/j.isci.2023.107300
  19. J Cell Physiol. 2023 Aug 10.
    Mettl14-mediated m6 A modification regulates the abnormal differentiation of small intestinal epithelial stem cells in diabetic state.
    Ti-Dong Shan, Yue Han, Ming-Quan Song, Li Chen.
      Diabetes mellitus (DM) and its related complications are a global epidemic characterized by high morbidity and mortality. However, little is known about diabetic enteropathy (DE) and its the potential underlying mechanism. Intestinal epithelial stem cells (IESCs) were harvested from experimental mice, and the levels of dominant N6-methyladenosine (m6 A)-related enzyme were detected by RT-PCR, Western blotting, immunohistochemistry. The role of Mettl14 in the abnormal differentiation of intestinal epithelial cells (IECs) during DM was confirmed by knockdown experiments. RT-PCR, MeRIP, and bioinformatics analysis were carried out to confirm the downstream target of Mettl14. Through bioinformatics analysis, RT-PCR, and Western blotting, we further analyzed the differentiation-related gene in the IECs from mice with DM. In this study, the levels of Mettl14 and m6 A were higher in db/db mice than that in control mice. And abnormal differentiation of IECs in DM was associated with Mettl14 overexpression. Additionally, Mettl14 is a major determinant of IESCs identity and organoid-forming upon DM state. Mechanistically, we revealed that the candidate binding target of Mettl14 was Fzd2 mRNA and affected Fzd2 stability. Moreover, Mettl14 downregulation was observed to attenuate the abnormal differentiation of IECs through modulating Fzd2 m6A modification in DM state. Together, our results provide definitive evidence for the essential role of Mettl14 in differentiation of IESCs in DM state.
    Keywords:  Mettl14; diabetes mellitus; differentiation; intestinal epithelial stem cell
    DOI:  https://doi.org/10.1002/jcp.31090
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