bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒08‒28
35 papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
  2. METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.
  3. METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way.
  4. Comprehensive analysis of transcriptome-wide m6A methylome in intermediate-stage Esophageal squamous cell carcinoma.
  5. N6-methyladenosine-mediated upregulation of LINC00520 accelerates breast cancer progression via regulating miR-577/POSTN axis and downstream ILK/AKT/mTOR signaling pathway.
  6. Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia.
  7. Multifaceted Roles of the N6-Methyladenosine RNA Methyltransferase METTL3 in Cancer and Immune Microenvironment.
  8. m6A regulator-mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in patients with intracranial aneurysms.
  9. m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.
  10. M6A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy Response in Hepatocellular Carcinoma.
  11. The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction.
  12. Role of RNA m6A modification in titanium dioxide nanoparticle-induced acute pulmonary injury: An in vitro and in vivo study.
  13. ALKBH5-mediated m6A modification of circCCDC134 facilitates cervical cancer metastasis by enhancing HIF1A transcription.
  14. METTL3 enhances PNN mRNA stability through m6A modification to augment tumorigenesis of colon adenocarcinoma.
  15. Regulation of N6-methyladenosine (m6A) RNA methylation in microglia-mediated inflammation and ischemic stroke.
  16. N6-Methyladenosine regulator RBM15B acts as an independent prognostic biomarker and its clinical significance in uveal melanoma.
  17. Expression profiles of m6A RNA methylation regulators, PD-L1 and immune infiltrates in gastric cancer.
  18. Dynamic Alteration Profile and New Role of RNA m6A Methylation in Replicative and H2O2-Induced Premature Senescence of Human Embryonic Lung Fibroblasts.
  19. N(6)-methyladenosine modification: A vital role of programmed cell death in myocardial ischemia/reperfusion injury.
  20. Regulatory role of RNA N6-methyladenosine modifications during skeletal muscle development.
  21. High-throughput microarray reveals the epitranscriptome-wide landscape of m6A-modified circRNA in oral squamous cell carcinoma.
  22. Identification and characterization of N6-methyladenosine circular RNAs in the spinal cord of morphine-tolerant rats.
  23. Crosstalk between m6A regulators and mRNA during cancer progression.
  24. METTL3 inhibition reduces m6 A levels and prevents allogeneic CD4+ T-cell responses.
  25. Research progress of m6A regulation during animal growth and development.
  26. Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases.
  27. Multiple Roles of m6A RNA Modification in Translational Regulation in Cancer.
  28. RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives.
  29. m5C writer NSUN3 promotes tumor progression by regulating immune infiltration in HNSCC.
  30. The m6A-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Tumor Immune Infiltration in Ovarian Cancer.
  31. YT521-B homology domain family proteins as N6-methyladenosine readers in tumors.
  32. Protocol for the generation of HIV-1 genomic RNA with altered levels of N 6-methyladenosine.
  33. LRTCLS: low-rank tensor completion with Laplacian smoothing regularization for unveiling the post-transcriptional machinery of N6-methylation (m6A)-mediated diseases.
  34. Prognostic value of 12 m7G methylation-related miRNA markers and their correlation with immune infiltration in breast cancer.
  35. YTHDF3 Is Involved in the Diapause Process of Bivoltine Bombyx mori Strains by Regulating the Expression of Cyp307a1 and Cyp18a1 Genes in the Ecdysone Synthesis Pathway.
  1. Nat Metab. 2022 Aug;4(8): 1041-1054
    N6-methyladenosine (m6A) in 18S rRNA promotes fatty acid metabolism and oncogenic transformation.
    Hao Peng, Binbin Chen, Wei Wei, Siyao Guo, Hui Han, Chunlong Yang, Jieyi Ma, Lu Wang, Sui Peng, Ming Kuang, Shuibin Lin.
      Aberrant RNA modifications lead to dysregulated gene expression and cancer progression. Ribosomal RNA (rRNA) accounts for more than 80% of a cell's total RNA, but the functions and molecular mechanisms underlying rRNA modifications in cancers are poorly understood. Here, we show that the 18S rRNA N6-methyladenosine (m6A) methyltransferase complex METTL5-TRMT112 is upregulated in various cancer types and correlated with poor prognosis. In addition, we demonstrate the critical functions of METTL5 in promoting hepatocellular carcinoma (HCC) tumorigenesis in vitro and in mouse models. Mechanistically, depletion of METTL5-mediated 18S rRNA m6A modification results in impaired 80S ribosome assembly and decreased translation of mRNAs involved in fatty acid metabolism. We further reveal that ACSL4 mediates the function of METTL5 on fatty acid metabolism and HCC progression, and targeting ACSL4 and METTL5 synergistically inhibits HCC tumorigenesis in vivo. Our study uncovers mechanistic insights underlying mRNA translation control and HCC tumorigenesis through lipid metabolism remodeling and provides a molecular basis for the development of therapeutic strategies for HCC treatment.
    DOI:  https://doi.org/10.1038/s42255-022-00622-9
  2. Oncogene. 2022 Aug 20.
    METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.
    Qiu-Ying Du, Fu-Chun Huo, Wen-Qi Du, Xiao-Lin Sun, Xin Jiang, Lan-Sheng Zhang, Dong-Sheng Pei.
      N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.
    DOI:  https://doi.org/10.1038/s41388-022-02435-2
  3. BMC Pulm Med. 2022 Aug 25. 22(1): 324
    METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way.
    Xuejun Dou, Zhiyuan Wang, Weiqiang Lu, Libin Miao, Yuefeng Zhao.
      BACKGROUND: N6-methyladenosine (m6A) is the most common RNA modification, which plays a pivotal role in tumor development and progression. In this study, we assessed the role of m6A methyltransferase METTL3 in FRAS1-involved cell proliferation and colony formation of non-small cell lung cancer (NSCLC) cell lines.METHODS: Cell viability was analyzed by Cell Counting Kit (CCK-8) and colony formation. M6A RNA immunoprecipitation (IP), Ribosomal immunoprecipitation, RNA immunoprecipitation (RIP) were performed to verify the relationship between METTL3, FRAS1 and YTHDF1. Rescue experiments to confirm the regulatory mechanism of METTL3-FRAS1 promoted NSCLC cell proliferation through CDON by cooperating YTHDF1.
    RESULTS: We found that FRAS1 was correlated with poor prognosis in NSCLC patients, of which the transcript undergoes m6A modification regulated by METTL3. METTL3 silence reduced cell viability of NSCLC cells HCC827 and NCI-H1975, which could be restored by FRAS1 overexpression. The m6A modification of FRAS1 could be recognized by YTHDF1. FRAS1 silence or YTHDF1 silence could rescue the elevated NSCLC cell proliferation, colony formation, and tumor growth induced by METTL3 overexpression in vitro and in vivo.
    CONCLUSIONS: Our study reveals that METTL3-FRAS1 plays a crucial role in NSCLC cell proliferation, colony formation, and tumor growth through the regulation of CDON by cooperating YTHDF1.
    Keywords:  CDON; Cell proliferation; Colony formation; FRAS1; METTL3; Non-small cell lung cancer (NSCLC); YTHDF1
    DOI:  https://doi.org/10.1186/s12890-022-02119-3
  4. Pathol Res Pract. 2022 Aug 04. pii: S0344-0338(22)00299-0. [Epub ahead of print]237 154055
    Comprehensive analysis of transcriptome-wide m6A methylome in intermediate-stage Esophageal squamous cell carcinoma.
    Xiaoli Jia, Zhilong Zhang, Rongqiang Wei, Bin Li, Yiyang Chen, Jiang Li.
      N6-Methyladenosine (m6A) RNA methylation is the most prevalent post-transcriptional modification mechanism in humans and plays an important role in the pathogenesis of various tumors. However, the investigation of m6A modification in Esophageal squamous cell carcinoma (ESCC) remains in its infancy. Transcriptome-wide m6A changes were profiled using human m6A epitranscriptomic microarrays in ESCC tissues and adjacent normal tissues. Differentially m6A-methylated mRNAs, lncRNAs and Mid-size ncRNAs were identified, followed by functional enrichment analysis. Moreover, we also establish a competing endogenous RNA (ceRNA) network based on the m6A-related lncRNA growth arrest specific 5 (GAS5) specific transcript（NR_152533）. The results suggested that RALYL may be a target gene for miR-3912-5p, and that GAS5 regulated RALYL expression by binding to miR-3912-5p.
    Keywords:  Esophageal squamous cell carcinoma; Human m6A epitranscriptomic microarrays; Long non-coding RNA GAS5; MiR-3912–5p; N6-methyladenosine (m6A); RALYL
    DOI:  https://doi.org/10.1016/j.prp.2022.154055
  5. Arch Biochem Biophys. 2022 Aug 23. pii: S0003-9861(22)00265-X. [Epub ahead of print] 109381
    N6-methyladenosine-mediated upregulation of LINC00520 accelerates breast cancer progression via regulating miR-577/POSTN axis and downstream ILK/AKT/mTOR signaling pathway.
    Yang Guo, Liang Feng.
      Various lncRNAs have been reported to be closely associated with cancer initiation and progression in breast cancer (BC), including LINC00520. However, the role and underlying mechanisms by which LINC00520 affects BC aggressiveness have not been fully delineated, and this study aimed to explore this issue. Through performing qRT-PCR analysis, we proved that LINC00520 was significantly upregulated in BC tissues and cells, compared with normal tissues and cells. Higher expression of LINC00520 was closely related to higher tumor grade, poor differentiation and shorter survival in BC patients. Next, the loss-of-function experiments evidenced that silencing LINC00520 suppressed BC cell proliferation, migration and epithelial-mesenchymal transition (EMT) in vitro, and inhibited tumorigenesis in vivo. Interestingly, we found that LINC00520 expression was positively regulated by METTL3-mediated N6-methyladenosine(m6A) modification in BC. Furthermore, we identified the tumor-suppressor miR-577 as the binding target of LINC00520 in BC. Mechanistically, LINC00520 elevated POSTN level via sponging miR-577, resulting in the activation of the downstream tumor-promoting ILK/Akt/mTOR pathway. Finally, the rescuing experiments evidenced that both POSTN knockdown and ILK/Akt/mTOR pathway inhibitor OSU-T315 abrogated the promoting effects of miR-577 ablation on the malignant phenotypes in BC. Collectively, this study firstly verified that LINC00520 acted as a ceRNA of miR-577 to advance BC aggressiveness in a m6A-dependent manner, providing novel biomarkers for BC diagnosis and therapy.
    Keywords:  Breast cancer; ILK/Akt/mTOR pathway; LINC00520; N6-methyladenosine modification; POSTN
    DOI:  https://doi.org/10.1016/j.abb.2022.109381
  6. Biomark Res. 2022 Aug 23. 10(1): 64
    Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia.
    Wei-Wei Liu, Hao Wang, Xiao-Yu Zhu.
      N6-methyladenosine (m6A), the most prevalent epigenetic modification of RNA in mammals, has become a hot topic throughout recent years. m6A is involved with every links of the RNA fate, including RNA splicing, nuclear export, translation and stability. Due to the reversible and dynamic regulatory network composed of 'writers' (methylase), 'erasers' (demethylase) and 'readers' (m6A binding proteins), m6A has been deemed as an essential modulator in vast physiological and pathological processes. Previous studies have shown that aberrant expression and dysfunction of these regulators are implicated in diverse tumors, exemplified by hematological malignancies. However, we should hold a dialectic perspective towards the influence of m6A modification on leukemogenesis. Given that m6A itself is neither pro-oncogenic nor anti-oncogenic, whether the modifications promote hematological homeostasis or malignancies occurrence and progression is dependent on the specific targets it regulates. Ample evidence supports the role of m6A in maintaining normal hematopoiesis and leukemogenesis, thereby highlighting the therapeutic potential of intervention in m6A modification process for battling leukemia. In this review, we introduce the advances of m6A modification and summarize the biological functions of m6A in RNA metabolism. Then we discuss the significance of several well-studied m6A regulators in modulating normal and malignant hematopoiesis, with focus on the therapeutic potentials of targeting these regulators for battling hematopoietic malignancies.
    Keywords:  Hematopoiesis; Hematopoietic stem cells; Leukemia; N6-methyladenosine
    DOI:  https://doi.org/10.1186/s40364-022-00410-3
  7. Biomolecules. 2022 Jul 28. pii: 1042. [Epub ahead of print]12(8):
    Multifaceted Roles of the N6-Methyladenosine RNA Methyltransferase METTL3 in Cancer and Immune Microenvironment.
    Chenxi Hu, Jiacheng Liu, Yue Li, Wei Jiang, Ding Ji, Wei Liu, Teng Ma.
      As the most abundant internal mRNA modification in eukaryotic cells, N6-methyladenosine (m6A) has emerged as an important regulator of gene expression and has a profound impact on cancer initiation and progression. mRNA m6A modification is regulated by m6A methyltransferases, demethylases and reader proteins to fine tune gene expression at the post-transcriptional level. The most well-studied m6A methyltransferase, METTL3, plays critical roles in regulating gene expression and affecting the outcome of various cancers. In this review, we discuss the multifaceted roles of METTL3 in regulating specific molecular signaling pathways in different types of cancers and the recent progress on how METTL3 impacts the tumor immune microenvironment. Finally, we discuss future directions and the potential for therapeutic targeting of METTL3 in cancer treatment.
    Keywords:  METTL3; RNA modification; m6A; methyltransferase; tumor immune microenvironment
    DOI:  https://doi.org/10.3390/biom12081042
  8. Front Neurol. 2022 ;13 889141
    m6A regulator-mediated RNA methylation modification patterns and immune microenvironment infiltration characterization in patients with intracranial aneurysms.
    Aierpati Maimaiti, Mirzat Turhon, Xiaojiang Cheng, Riqing Su, Kaheerman Kadeer, Aximujiang Axier, Dilimulati Ailaiti, Yirizhati Aili, Rena Abudusalamu, Ajimu Kuerban, Zengliang Wang, Maimaitili Aisha.
      Background: The role of epigenetic modulation in immunity is receiving increased recognition-particularly in the context of RNA N6-methyladenosine (m6A) modifications. Nevertheless, it is still uncertain whether m6A methylation plays a role in the onset and progression of intracranial aneurysms (IAs). This study aimed to establish the function of m6A RNA methylation in IA, as well as its correlation with the immunological microenvironment.Methods: Our study included a total of 97 samples (64 IA, 33 normal) in the training set and 60 samples (44 IA, 16 normal) in the validation set to systematically assess the pattern of RNA modifications mediated by 22 m6A regulators. The effects of m6A modifications on immune microenvironment features, i.e., immune response gene sets, human leukocyte antigen (HLA) genes, and infiltrating immune cells were explored. We employed Lasso, machine learning, and logistic regression for the purpose of identifying an m6A regulator gene signature of IA with external data validation. For the unsupervised clustering analysis of m6A modification patterns in IA, consensus clustering methods were employed. Enrichment analysis was used to assess immune response activity along with other functional pathways. The identification of m6A methylation markers was identified based on a protein-protein interaction network and weighted gene co-expression network analysis.
    Results: We identified an m6A regulator signature of IGFBP2, IGFBP1, IGF2BP2, YTHDF3, ALKBH5, RBM15B, LRPPRC, and ELAVL1, which could easily distinguish individuals with IA from healthy individuals. Unsupervised clustering revealed three m6A modification patterns. Gene enrichment analysis illustrated that the tight junction, p53 pathway, and NOTCH signaling pathway varied significantly in m6A modifier patterns. In addition, the three m6A modification patterns showed significant differences in m6A regulator expression, immune microenvironment, and bio-functional pathways. Furthermore, macrophages, activated T cells, and other immune cells were strongly correlated with m6A regulators. Eight m6A indicators were discovered-each with a statistically significant correlation with IA-suggesting their potential as prognostic biological markers.
    Conclusion: Our study demonstrates that m6A RNA methylation and the immunological microenvironment are both intricately correlated with the onset and progression of IA. The novel insight into patterns of m6A modification offers a foundation for the development of innovative treatment approaches for IA.
    Keywords:  epigenetics; immune microenvironment; immunity; intracranial aneurysm; m6A RNA methylation
    DOI:  https://doi.org/10.3389/fneur.2022.889141
  9. Cancers (Basel). 2022 Aug 21. pii: 4035. [Epub ahead of print]14(16):
    m6A Methylation Regulators Are Predictive Biomarkers for Tumour Metastasis in Prostate Cancer.
    Yingchun Liang, Xiaohua Zhang, Chenkai Ma, Jimeng Hu.
      Prostate cancer (PCa) is one of the most common cancers in men. Usually, most PCas at initial diagnosis are localized and hormone-dependent, and grow slowly. Patients with localized PCas have a nearly 100% 5-year survival rate; however, the 5-year survival rate of metastatic or progressive PCa is still dismal. N6-methyladenosine (m6A) is the most common post-transcriptional mRNA modification and is dynamically regulated by m6A regulators. A few studies have shown that the abnormal expression of m6A regulators is significantly associated with cancer progression and immune cell infiltration, but the roles of these regulators in PCa remain unclear. Here, we examined the expression profiles and methylation levels of 21 m6A regulators across the Cancer Genome Atlas (TCGA), 495 PCas by consensus clustering, and correlated the expression of m6A regulators with PCa progression and immune cell infiltration. Consensus clustering was applied for subtyping Pca samples into clusters based on the expression profiles of m6A regulators. Each subtype's signature genes were obtained by a pairwise differential expression analysis. Featured pathways of m6A subtypes were predicted by Gene Ontology. The m6A score was developed to predict m6A activation. The association of the m6A score with patients' survival, metastasis and immune cell infiltration was also investigated. We identified three distinct clusters in PCa based on the expression profiles of 21 m6A regulators by consensus clustering. The differential expression and pathway analyses on the three clusters uncovered the m6A regulators involved in metabolic processes and immune responses in PCa. Moreover, we developed an m6A score to evaluate the m6A regulator activation for PCa. The m6A score is significantly associated with Gleason scores and metastasis in PCa. The predictive capacity of the m6A score on PCa metastasis was also validated in another independent cohort with an area under the curve of 89.5%. Hence, our study revealed the critical role of m6A regulators in PCa progression and the m6A score is a promising predictive biomarker for PCa metastasis.
    Keywords:  biomarker; immune cell infiltration; m6A; metastasis; methylation; prostate cancer
    DOI:  https://doi.org/10.3390/cancers14164035
  10. J Oncol. 2022 ;2022 2513813
    M6A Modifier-Mediated Methylation Characterized by Diverse Prognosis, Tumor Microenvironment, and Immunotherapy Response in Hepatocellular Carcinoma.
    Fei Liu, Xinyue Zhang, Ziyu Liu, Weiye Cai, Chao Song, Yan Jiang, Ji Yin, Zongchao Liu, Chenyi Huang.
      Objective: Emerging evidence highlights the clinical implications of N6-methyladenosine (m6A) modification in HCC. Yet, the roles of m6A modification in modulating cancer immunity and shaping tumor microenvironment (TME) are undefined in hepatocellular carcinoma (HCC).Methods: Here, m6A modification classification was determined for HCC through 23 m6A modifier levels by employing consensus clustering approach. Prognosis analysis was presented for comparing the differences in survival outcomes. The ssGSEA and ESTIMATE approaches were adopted for evaluating the abundances of tumor-infiltrating immune cell populations. The m6A scoring system was computed for reflecting m6A modification classification via PCA algorithm.
    Results: Three m6A modifier-mediated modification patterns were established among HCC specimens, which were characterized by different prognosis, signaling pathways, and TME features. After extracting m6A phenotype-associated DEGs, we determined m6A scores in individual HCC and stratified patients into high- and low-score groups. Patients with low m6A score displayed the survival advantage and higher sensitivity to gemcitabine. Moreover, those with low m6A score possessed the better anti-PD-1/PD-L1 therapeutic response in the IMvigor210 immunotherapy cohort.
    Conclusion: Our findings highlighted that m6A modification exerted a nonnegligible role in remodeling diverse and complex TME. Quantification of the m6A modification patterns of individual HCC may enhance the comprehension of TME features and facilitate immunotherapeutic plans.
    DOI:  https://doi.org/10.1155/2022/2513813
  11. Antioxidants (Basel). 2022 Aug 04. pii: 1521. [Epub ahead of print]11(8):
    The Potential Role of m6A in the Regulation of TBI-Induced BGA Dysfunction.
    Peizan Huang, Min Liu, Jing Zhang, Xiang Zhong, Chunlong Zhong.
      The brain-gut axis (BGA) is an important bidirectional communication pathway for the development, progress and interaction of many diseases between the brain and gut, but the mechanisms remain unclear, especially the post-transcriptional regulation of BGA after traumatic brain injury (TBI). RNA methylation is one of the most important modifications in post-transcriptional regulation. N6-methyladenosine (m6A), as the most abundant post-transcriptional modification of mRNA in eukaryotes, has recently been identified and characterized in both the brain and gut. The purpose of this review is to describe the pathophysiological changes in BGA after TBI, and then investigate the post-transcriptional bidirectional regulation mechanisms of TBI-induced BGA dysfunction. Here, we mainly focus on the characteristics of m6A RNA methylation in the post-TBI BGA, highlight the possible regulatory mechanisms of m6A modification in TBI-induced BGA dysfunction, and finally discuss the outcome of considering m6A as a therapeutic target to improve the recovery of the brain and gut dysfunction caused by TBI.
    Keywords:  brain-gut axis; m6A RNA modification; traumatic brain injury
    DOI:  https://doi.org/10.3390/antiox11081521
  12. Environ Pollut. 2022 Aug 22. pii: S0269-7491(22)01200-3. [Epub ahead of print] 119986
    Role of RNA m6A modification in titanium dioxide nanoparticle-induced acute pulmonary injury: An in vitro and in vivo study.
    Fengkai Ruan, Changqian Liu, Yi Wang, Xisen Cao, Zhen Tang, Jiaying Xu, Jie Zeng, Hanying Yin, Naying Zheng, Chunyan Yang, Zhenghong Zuo, Chengyong He.
      RNA N6-methyladenosine (m6A) modification regulates the cell stress response and homeostasis, but whether titanium dioxide nanoparticle (nTiO2)-induced acute pulmonary injury is associated with the m6A epitranscriptome and the underlying mechanisms remain unclear. Here, the potential association between m6A modification and the bioeffects of several engineered nanoparticles (nTiO2, nAg, nZnO, nFe2O3, and nCuO) were verified thorough in vitro experiments. nFe2O3, nZnO, and nTiO2 exposure significantly increased the global m6A level in A549 cells. Our study further revealed that nTiO2 can induce m6A-mediated acute pulmonary injury. Mechanistically, nTiO2 exposure promoted methyltransferase-like 3 (METTL3)-mediated m6A signal activation and thus mediated the inflammatory response and IL-8 release through the degeneration of anti-Mullerian hormone (AMH) and Mucin 5 B (MUC5B) mRNAs in a YTH m6A RNA-binding protein 2 (YTHDF2)-dependent manner. Moreover, nTiO2 exposure stabilized METTL3 protein by the lipid reactive oxygen species (ROS)-activated ERK1/2 pathway. The scavenging of ROS with ferrostatin-1 (Fer-1) alleviates the ERK1/2 activation, m6A upregulation, and the inflammatory response caused by nTiO2 both in vitro and in vivo. In conclusion, our study demonstrates that m6A is a potential intervention target for alleviating the adverse effects of nTiO2-induced acute pulmonary injury in vitro and in vivo, which has far-reaching implications for protecting human health and improving the sustainability of nanotechnology.
    Keywords:  METTL3; Nanosafety; Oxidative stress; RNA m(6)A; Titanium dioxide nanoparticles
    DOI:  https://doi.org/10.1016/j.envpol.2022.119986
  13. J Exp Clin Cancer Res. 2022 Aug 26. 41(1): 261
    ALKBH5-mediated m6A modification of circCCDC134 facilitates cervical cancer metastasis by enhancing HIF1A transcription.
    Leilei Liang, Yunshu Zhu, Jian Li, Jia Zeng, Lingying Wu.
      BACKGROUND: Metastasis is the main cause of mortality in cervical cancer (CC). Circular RNAs (circRNAs) have been demonstrated to play a crucial role in carcinoma biology. However, the expression and function of circRNAs in cervical cancer metastasis are still unclear.METHODS: In the present study, we identified a circRNA with an N6-methyladenosine (m6A) modification, circCCDC134, whose expression was increased in CC tissues by circRNA-Seq and qPCR. CircCCDC134 upregulation in CC was fine-tuned by ALKBH5-mediated m6A modification, which enhanced its stability in a YTHDF2-dependent manner. The functional experiments illustrated that circCCDC134 enhanced tumour proliferation and metastasis in vitro and in vivo. For the comprehensive identification of RNA-binding proteins, circRNA pull-down and mass spectrometry (ChIRP-MS), chromatin immunoprecipitation-seq (Chip-seq), RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were used to perform mechanistic investigations.
    RESULTS: The results revealed that circCCDC134 recruited p65 in the nucleus and acted as a miR-503-5p sponge to regulate the expression of MYB in the cytoplasm, ultimately stimulating HIF1A transcription and facilitating CC growth and metastasis.
    CONCLUSION: These findings indicate that circCCDC134 is an important therapeutic target and provide new regulatory model insights for exploring the carcinogenic mechanism of circCCDC134 in CC.
    Keywords:  Cervical cancer metastasis; circCCDC134; m6A methylation; miR-503-5p; p65
    DOI:  https://doi.org/10.1186/s13046-022-02462-7
  14. Exp Physiol. 2022 Aug 22.
    METTL3 enhances PNN mRNA stability through m6A modification to augment tumorigenesis of colon adenocarcinoma.
    Min He, Danling Jiang, Anying Xun, Jian Yang, Qianjiang Luo, Huihua Wu.
      NEW FINDINGS: What is the central question of this study? This study focuses on the role of Pinin (PNN) in the malignant phenotype of colon adenocarcinoma cells and the underlying mechanism. What is the main finding and its importance? PNN can be stabilized and upregulated by METTL3, which promotes glycolysis in COAD and augments cell proliferation, migration and invasiveness. METTL3 and PNN might serve as potential targets for the treatment of COAD.ABSTRACT: Colon adenocarcinoma (COAD) is a fatal malignancy with high morbidity and mortality rates globally. Pinin (PNN), a desmosome associated protein, has been revealed as a tumor driver in several malignancies. This study aims to probe the expression and role of PNN in COAD and the underlying mechanism. PNN expressed at high levels in clinically collected COAD tumors and was linked to poor prognosis of patients. Downregulation of PNN reduced glucose uptake, lactate production and ATP levels in COAD cells and suppressed cell proliferation, migration, and invasiveness. Methyltransferase like 3 (METTL3) was positively associated with PNN levels in COAD tumor tissues. The RNA immunoprecipitation and m6A quantification assays indicated that METTL3 enhanced PNN mRNA stability and expression in COAD through m6A modification with the involvement of m6A "reader" protein YTHDF1. Downregulation of METTL3 reduced COAD cell glycolysis and proliferation in vitro and suppressed growth and metastasis of xenograft tumors in vivo, but further overexpression of PNN restored malignant behaviors of COAD cells and tumor growth. In summary, this study demonstrates that METTL3 promotes PNN mRNA stability and expression in COAD through m6A modification, which augments glycolysis and proliferation of COAD cells and leads to the resultant tumor progression. This article is protected by copyright. All rights reserved.
    Keywords:  METTL3; PNN; colon adenocarcinoma; glycolysis; m6A modification
    DOI:  https://doi.org/10.1113/EP090273
  15. Front Cell Neurosci. 2022 ;16 955222
    Regulation of N6-methyladenosine (m6A) RNA methylation in microglia-mediated inflammation and ischemic stroke.
    Fangfang Zhang, Yuanyuan Ran, Muhammad Tahir, Zihan Li, Jianan Wang, Xuechai Chen.
      N6-methyladenosine (m6A) is the most abundant post-transcription modification, widely occurring in eukaryotic mRNA and non-coding RNA. m6A modification is highly enriched in the mammalian brain and is associated with neurological diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). Ischemic stroke (IS) was discovered to alter the cerebral m6A epi-transcriptome, which might have functional implications in post-stroke pathophysiology. Moreover, it is observed that m6A modification could regulate microglia's pro-inflammatory and anti-inflammatory responses. Given the critical regulatory role of microglia in the inflammatory processes in the central nervous system (CNS), we speculate that m6A modification could modulate the post-stroke microglial inflammatory responses. This review summarizes the vital regulatory roles of m6A modification in microglia-mediated inflammation and IS. Stroke is associated with a high recurrence rate, understanding the relationship between m6A modification and stroke may help stroke rehabilitation and develop novel therapies in the future.
    Keywords:  RNA methylation; ischemic stroke; microglia; neuroinflammation; polarization
    DOI:  https://doi.org/10.3389/fncel.2022.955222
  16. Front Immunol. 2022 ;13 918522
    N6-Methyladenosine regulator RBM15B acts as an independent prognostic biomarker and its clinical significance in uveal melanoma.
    Tianyu Wang, Jianhao Bai, Yuanyuan Zhang, Yawen Xue, Qing Peng.
      Uveal melanoma (UM) is the most frequent intraocular malignant tumor in adults. N6-Methyladenosine (m6A) methylation is recognized as the most critical epigenetic change and is implicated in the development of many malignancies. However, its prognostic value in UM is poorly understood. RNA-seq and clinical data from The Cancer Genome Atlas (TCGA) help us better understand the relationship between m6A regulators and UM patients. Herein, four UM groups established by consensus clustering were shown to have different immune cell infiltrations and prognostic survival. Five m6A regulators, including RBM15B, IGF2BP1, IGF2BP2, YTHDF3, and YTHDF1, were associated with the prognosis of UM patients. Intriguingly, RBM15B was confirmed to be the only independent prognostic factor for UM and it was significantly correlated with clinicopathologic characteristics of UM. Notably, RBM15B expression was significantly negatively correlated with immune checkpoints. Furthermore, LINC00665/hsa-let-7b-5p/RBM15B axis and LINC00638/hsa-miR-103a-3p/RBM15B axis were found to be potential prognostic biomarkers in UM. In a nutshell, this work, through bioinformatics analysis, systematically described the gene signatures and prognostic values of m6A regulators. RBM15B is an independent protective prognostic factor, which may help us better understand the crosstalk within UM.
    Keywords:  RBM15B; TCGA; m6A (N6-methyladenosine); prognosis; uveal melanoma
    DOI:  https://doi.org/10.3389/fimmu.2022.918522
  17. Front Oncol. 2022 ;12 970367
    Expression profiles of m6A RNA methylation regulators, PD-L1 and immune infiltrates in gastric cancer.
    Zhiyuan Xu, Qiuli Chen, Lilu Shu, Chunye Zhang, Wenjun Liu, Peter Wang.
      Gastric cancer is the fourth most frequent cancer and has a high death rate. Immunotherapy represented by PD-1 has brought hope for the treatment of advanced gastric cancer. Methylation of the m6A genes is linked to the onset and progression of numerous cancers, but there are few studies on gastric cancer. The main purpose of this study aims to analyze the relationship between m6A RNA methylation regulators, PD-L1, prognosis and tumor immune microenvironment (TIME) in gastric cancer. The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEx) databases were used to acquire transcriptomic data and clinical information from gastric cancer patients. The changes in m6A regulator expression levels in gastric cancer tissues and normal tissues were studied. Consensus clustering analysis was used to separate gastric cancer samples into two categories. We employed Least Absolute Shrinkage, Selection Operator (LASSO) Cox regression analysis, Gene Set Enrichment Analysis (GSEA), and cBioPortal to analyze the m6A regulators, PD-L1 and TIME in gastric cancer. In gastric cancer tissues, the majority of m6A regulatory factors are considerably overexpressed. Two gastric cancer subgroups (Cluster1/2) based on consensus clustering of 21 m6A regulators. PD-L1 and PD-1 expression levels were significantly higher in gastric cancer tissues, and they were significantly linked with METTL3, WTAP, HNRNPD, ZC3H7B, METTL14, FTO, PCIF1, HNRNPC, YTHDF1 and YTDHF2. Cluster1 showed a large increase in resting memory CD4+ T cells, regulatory T cells, naïve B cells, active NK cells, and resting Mast cells. Cluster1 and Cluster2 were shown to be involved in numerous critical signaling pathways, including base excision repair, cell cycle, nucleotide excision repair, RNA degradation, and spliceosome pathways. Gastric cancer RiskScores based on prognostic factors have been found as independent prognostic indicators. The amount of tumor-infiltrating immune cells is dynamically affected by changes in the copy number of m6A methylation regulators associated with TIME.
    Keywords:  PD1; PDL1; TME; gastric cancer; m6A; time
    DOI:  https://doi.org/10.3389/fonc.2022.970367
  18. Int J Mol Sci. 2022 Aug 17. pii: 9271. [Epub ahead of print]23(16):
    Dynamic Alteration Profile and New Role of RNA m6A Methylation in Replicative and H2O2-Induced Premature Senescence of Human Embryonic Lung Fibroblasts.
    Fan Wu, Luyun Zhang, Caiyun Lai, Xinyue Peng, Susu Yu, Cheng Zhou, Bo Zhang, Wenjuan Zhang.
      N6-methyladenosine (m6A) methylation is one of the most common RNA modifications, regulating RNA fate at the posttranscriptional level, and is closely related to cellular senescence. Both models of replicative and premature senescence induced by hydrogen peroxide (H2O2) were used to detect m6A regulation during the senescence of human embryonic lung fibroblasts (HEFs). The ROS level accumulated gradually with senescence, leading to normal replicative senescence. H2O2-treated cells had dramatically increased ROS level, inducing the onset of acute premature senescence. Compared with replicative senescence, ROS changed the expression profiles for m6A-related enzymes and binding proteins, including higher levels of METTL3, METTL14, WTAP, KIAA1429, and FTO, and lower levels of METTL16, ALKBH5, YTHDC1, and YTHDF1/2/3 in the premature senescence persistence group, respectively. Meanwhile, senescent cells decreased total m6A content and RNA methylation enzymes activity, regardless of replicative or premature senescence. Moreover, specific m6A methylation levels regulated the expression of SIRT3, IRS2, and E2F3 between replicative and premature senescence separately. Taken together, differential m6A epitranscription microenvironment and the targeted genes can be used as epigenetic biomarkers to cell senescence and the related diseases, offering new clues for the prevention and intervention of cellular senescence.
    Keywords:  RNA methylation; m6A; oxidative stress; premature senescence
    DOI:  https://doi.org/10.3390/ijms23169271
  19. Int J Cardiol. 2022 Aug 21. pii: S0167-5273(22)01252-9. [Epub ahead of print]
    N(6)-methyladenosine modification: A vital role of programmed cell death in myocardial ischemia/reperfusion injury.
    Jian Wang, Yanyan Li, Song Zhang.
      N(6)-methyladenosine (m6A) modification is closely associated with myocardial ischemia/reperfusion injury (MIRI). As the most common modification among RNA modifications, the reversible m6A modification is processed by methylase ("writers") and demethylase ("erasers"). The biological effects of RNA modified by m6A are regulated under the corresponding RNA binding proteins (RBPs) ("readers"). m6A modification regulates the whole process of RNA, including transcription, processing, splicing, nuclear export, stability, degradation, and translation. Programmed cell death (PCD) is a regulated mechanism that maintains the internal environment's stability. PCD plays an essential role in MIRI, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. However, the relationship between PCD modified with m6A and MIRI is still not clear. This review summarizes the regulators of m6A modification and their bioeffects on PCD in MIRI.
    Keywords:  Myocardial ischemia/reperfusion injury; Programmed cell death; m(6)A modification
    DOI:  https://doi.org/10.1016/j.ijcard.2022.08.042
  20. Front Cell Dev Biol. 2022 ;10 929183
    Regulatory role of RNA N6-methyladenosine modifications during skeletal muscle development.
    Baojun Yu, Jiamin Liu, Juan Zhang, Tong Mu, Xiaofang Feng, Ruoshuang Ma, Yaling Gu.
      Functional cells in embryonic myogenesis and postnatal muscle development undergo multiple stages of proliferation and differentiation, which are strict procedural regulation processes. N6-methyladenosine (m6A) is the most abundant RNA modification that regulates gene expression in specific cell types in eukaryotes and regulates various biological activities, such as RNA processing and metabolism. Recent studies have shown that m6A modification-mediated transcriptional and post-transcriptional regulation plays an essential role in myogenesis. This review outlines embryonic and postnatal myogenic differentiation and summarizes the important roles played by functional cells in each developmental period. Furthermore, the key roles of m6A modifications and their regulators in myogenesis were highlighted, and the synergistic regulation of m6A modifications with myogenic transcription factors was emphasized to characterize the cascade of transcriptional and post-transcriptional regulation during myogenesis. This review also discusses the crosstalk between m6A modifications and non-coding RNAs, proposing a novel mechanism for post-transcriptional regulation during skeletal muscle development. In summary, the transcriptional and post-transcriptional regulatory mechanisms mediated by m6A and their regulators may help develop new strategies to maintain muscle homeostasis, which are expected to become targets for animal muscle-specific trait breeding and treatment of muscle metabolic diseases.
    Keywords:  N6-methyladenosine (m6A) modification; epigenetic; myogenesis; skeletal muscle development; transcriptional regulation
    DOI:  https://doi.org/10.3389/fcell.2022.929183
  21. BMC Genomics. 2022 Aug 23. 23(1): 611
    High-throughput microarray reveals the epitranscriptome-wide landscape of m6A-modified circRNA in oral squamous cell carcinoma.
    Wei Zhao, Jingwen Liu, Jie Wu, Xiaozhou Ma, Xi Wang, Leyu Zhang, Zhe Han, Jianming Yang, Yameng Cui, Xin Hu, Jiayin Deng.
      BACKGROUND: Emerging transcriptome-wide high-throughput screenings reveal the landscape and functions of RNAs, such as circular RNAs (circRNAs), in human cancer. In addition, the post-transcriptional RNA internal modifications, especially N6-methyladenosine (m6A), greatly enrich the variety of RNAs metabolism. However, the m6A modification on circRNAs has yet to be addressed.RESULTS: Here, we report an epitranscriptome-wide mapping of m6A-modified circRNAs (m6A-circRNA) in oral squamous cell carcinoma (OSCC). Utilizing the data of m6A methylated RNA immunoprecipitation sequencing (MeRIP-seq) and m6A-circRNAs microarray, we found that m6A-circRNAs exhibited particular modification styles in OSCC, which was independent of m6A-mRNA. Besides, m6A modification on circRNAs frequently occurred on the long exons in the front part of the coding sequence (CDS), which was distinct from m6A-mRNA that in 3'-UTR or stop codon.
    CONCLUSION: In conclusion, our work preliminarily demonstrates the traits of m6A-circRNAs, which may bring enlighten for the roles of m6A-circRNAs in OSCC.
    Keywords:  Circular RNA; MeRIP-Seq.; N6-Methyladenosine; Oral squamous cell carcinoma; m6A-circRNAs
    DOI:  https://doi.org/10.1186/s12864-022-08806-z
  22. Front Neurosci. 2022 ;16 967768
    Identification and characterization of N6-methyladenosine circular RNAs in the spinal cord of morphine-tolerant rats.
    Manyu Xing, Meiling Deng, Yufei Shi, Jiajia Dai, Tong Ding, Zongbin Song, Wangyuan Zou.
      Morphine tolerance (MT) is a tricky problem, the mechanism of it is currently unknown. Circular RNAs (circRNAs) serve significant functions in the biological processes (BPs) of the central nervous system. N6-methyladenosine (m6A), as a key post-transcriptional modification of RNA, can regulate the metabolism and functions of circRNAs. Here we explore the patterns of m6A-methylation of circRNAs in the spinal cord of morphine-tolerant rats. In brief, we constructed a morphine-tolerant rat model, performed m6A epitranscriptomic microarray using RNA samples collected from the spinal cords of morphine-tolerant rats and normal saline rats, and implemented the bioinformatics analysis. In the spinal cord of morphine-tolerant rats, 120 circRNAs with different m6A modifications were identified, 54 of which were hypermethylated and 66 of which were hypomethylated. Functional analysis of these m6A circRNAs found some important pathways involved in the pathogenesis of MT, such as the calcium signaling pathway. In the m6A circRNA-miRNA networks, several critical miRNAs that participated in the occurrence and development of MT were discovered to bind to these m6A circRNAs, such as miR-873a-5p, miR-103-1-5p, miR-107-5p. M6A modification of circRNAs may be involved in the pathogenesis of MT. These findings may lead to new insights into the epigenetic etiology and pathology of MT.
    Keywords:  N6-methyladenosine; bioinformatics analysis; circRNAs; microarray; morphine tolerance
    DOI:  https://doi.org/10.3389/fnins.2022.967768
  23. Oncogene. 2022 Aug 25.
    Crosstalk between m6A regulators and mRNA during cancer progression.
    Xiaodong Niu, Yuan Yang, Yanming Ren, Shengtao Zhou, Qing Mao, Yuan Wang.
      m6A modification, the most abundant and widespread RNA modification, is present and involved in the occurrence and development of various cancers. To date, most studies have mainly focused on the roles of a single m6A regulator (writer/eraser/reader) in various cancers, but cumulative evidence shows that aberrant m6A regulators and m6A levels exert dual effects (promoting and/or inhibiting roles) in cancer progression. Recently, studies have investigated the direct interactions between different m6A regulators (writer/eraser and reader) and mRNAs in a variety of cancers. In this review, we summarize the functions of m6A regulators and their roles in various types of cancers. We further propose the possible crosstalk mechanisms (Writer-m6A-Reader-mRNA axis and Eraser-m6A-Reader-mRNA axis) between different m6A regulators and mRNAs during cancer progression. We also discuss the clinical potential of m6A regulator‑targeting strategies.
    DOI:  https://doi.org/10.1038/s41388-022-02441-4
  24. Immunol Cell Biol. 2022 Aug 25.
    METTL3 inhibition reduces m6 A levels and prevents allogeneic CD4+ T-cell responses.
    Shuang Li, Dawei Zou, Wenhao Chen, Gavin W Britz, Zhaoqian Liu, Yi-Lan Weng.
      Alloreactive CD4+ T cells play a central role in allograft rejection. However, the post-transcriptional regulation of the effector program in alloreactive CD4+ T cells is unclear. N6 -methyladenosine (m6 A) RNA modification is involved in various physiological and pathological processes. Herein, we investigated whether m6 A methylation plays a role in the allogeneic T-cell effector program. m6 A levels of CD4+ T cells from spleens, draining lymph nodes and skin allografts were determined in a skin transplantation model. The effects of a METTL3 inhibitor STM2457 on CD4+ T-cell characteristics including proliferation, cell cycle, cell apoptosis and effector differentiation were determined after stimulation of polyclonal and alloantigen-specific (TEa; TCR transgenic) CD4+ T cells with α-CD3/α-CD28 mAbs and cognate CB6F1 alloantigen, respectively. We found that graft-infiltrating CD4+ T cells expressed high m6 A levels. Administration of STM2457 reduced m6 A levels, inhibited T-cell proliferation, and suppressed effector differentiation of polyclonal CD4+ T cells. Alloreactive TEa cells challenged with 40μM STM2457 exhibited deficits in T-cell proliferation and Th1 cell differentiation, a cell cycle arrest in the G0 phase, and elevated cell apoptosis. Moreover, these impaired T-cell responses were associated with the diminished expression levels of transcription factors Ki67, c-Myc and T-bet. Therefore, METTL3 inhibition reduces the expression of several key transcriptional factors for the T-cell effector program and suppresses alloreactive CD4+ T-cell effector function and differentiation. Targeting m6 A-related enzymes and molecular machinery in CD4+ T-cells represents an attractive therapeutic approach to prevent allograft rejection.
    Keywords:  METTL3; N6-methyladenosine; STM2457; T cells; allogeneic response
    DOI:  https://doi.org/10.1111/imcb.12581
  25. Mol Cell Probes. 2022 Aug 22. pii: S0890-8508(22)00062-7. [Epub ahead of print] 101851
    Research progress of m6A regulation during animal growth and development.
    Yu Hengwei, Sayed Haidar Abbas Raza, Zhang Wenzhen, Yang Xinran, Hailah M Almohaimeed, Aliah R Alshanwani, Rasha Assiri, Waheeb S Aggad, Linsen Zan.
      Environmental factors, genetic factors, and epigenetics are involved in animal growth and development. Among them, methylation is one of the abundant modifications of epigenetics. N6-methyladenosine(m6A) is extensive in cellular RNA, of which mRNA is the most common internal modification. m6A modification regulates life activities dynamically and reversibly, including expressed genes, RNA metabolism, and protein translation. The m6A modifications are closely related to human diseases involving heart failure, tumors, and cancer. It is relatively in-depth in the medical field. However, there are few studies on its biochemical function in animals. We summarized the latest paper related to the chemical structure and role of the writers, the erasers, and the readers to study exerting dynamic regulation of m6A modification of animal growth and development. Furthermore, the key roles of m6A modification were reported in the process of RNA metabolism. Finally, the dynamic regulation of m6A modification in animal growth and development was reviewed, including brain development, fertility, fat deposition, and muscle production. It reveals the key roles of m6A modification and the regulation of gene expression, aiming to provide new ideas for m6A methylation in animal growth and development.
    Keywords:  Animal growth and development; RNA metabolism; m(6)A methylation
    DOI:  https://doi.org/10.1016/j.mcp.2022.101851
  26. Mol Ther Nucleic Acids. 2022 Sep 13. 29 426-461
    Emerging roles of the RNA modifications N6-methyladenosine and adenosine-to-inosine in cardiovascular diseases.
    IHD-EPITRAN Consortium
      Cardiovascular diseases lead the mortality and morbidity disease metrics worldwide. A multitude of chemical base modifications in ribonucleic acids (RNAs) have been linked with key events of cardiovascular diseases and metabolic disorders. Named either RNA epigenetics or epitranscriptomics, the post-transcriptional RNA modifications, their regulatory pathways, components, and downstream effects substantially contribute to the ways our genetic code is interpreted. Here we review the accumulated discoveries to date regarding the roles of the two most common epitranscriptomic modifications, N6-methyl-adenosine (m6A) and adenosine-to-inosine (A-to-I) editing, in cardiovascular disease.
    Keywords:  A-to-I editing; N6-methyladenosine; atherosclerosis; cardiac regeneration; cardiovascular medicine; epitranscriptomics; ischemic heart disease
    DOI:  https://doi.org/10.1016/j.omtn.2022.07.018
  27. Int J Mol Sci. 2022 Aug 11. pii: 8971. [Epub ahead of print]23(16):
    Multiple Roles of m6A RNA Modification in Translational Regulation in Cancer.
    Guillermo Fernandez Rodriguez, Bianca Cesaro, Alessandro Fatica.
      Despite its discovery in the early 1970s, m6A modification within mRNA molecules has only powerfully entered the oncology field in recent years. This chemical modification can control all aspects of the maturation of mRNAs, both in the nucleus and in the cytoplasm. Thus, the alteration in expression levels of writers, erasers, and readers may significantly contribute to the alteration of gene expression observed in cancer. In particular, the activation of oncogenic pathways can lead to an alteration of the global rate of mRNA translation or the selective translation of specific mRNAs. In both cases, m6A can play an important role. In this review, we highlight the role of m6A in the regulation of translation by focusing on regulatory mechanisms and cancer-related functions of this novel but still controversial field.
    Keywords:  cancer; m6A; translation
    DOI:  https://doi.org/10.3390/ijms23168971
  28. Biomedicines. 2022 Aug 08. pii: 1918. [Epub ahead of print]10(8):
    RNA Modifications in Gastrointestinal Cancer: Current Status and Future Perspectives.
    Xiaoting Zhang, Hao Su, Hongyan Chen, Qing Li, Xiaodong Liu, Lin Zhang, William Ka Kei Wu, Matthew Tak Vai Chan, Huarong Chen.
      Gastrointestinal (GI) cancer, referring to cancers of the digestive system such as colorectal cancer (CRC), gastric cancer (GC), and liver cancer, is a major cause of cancer-related deaths in the world. A series of genetic, epigenetic, and epitranscriptomic changes occur during the development of GI cancer. The identification of these molecular events provides potential diagnostic, prognostic, and therapeutic targets for cancer patients. RNA modification is required in the posttranscriptional regulation of RNA metabolism, including splicing, intracellular transport, degradation, and translation. RNA modifications such as N6-methyladenosine (m6A) and N1-methyladenosine (m1A) are dynamically regulated by three different types of regulators named methyltransferases (writers), RNA binding proteins (readers), and demethylases (erasers). Recent studies have pointed out that abnormal RNA modification contributes to GI tumorigenesis and progression. In this review, we summarize the latest findings on the functional significance of RNA modification in GI cancer and discuss the therapeutic potential of epitranscriptomic inhibitors for cancer treatment.
    Keywords:  RNA modification; gastrointestinal cancer; therapeutic target
    DOI:  https://doi.org/10.3390/biomedicines10081918
  29. Oral Dis. 2022 Aug 23.
    m5C writer NSUN3 promotes tumor progression by regulating immune infiltration in HNSCC.
    Shufang Jin, Jiayi Li, Yihan Shen, Yiqun Wu, Zhiyuan Zhang, Hailong Ma.
      OBJECTIVE: This study aimed to determine whether the RNA, 5-methylcytosine (m5C), is involved in the progression of head and neck squamous cell carcinoma (HNSCC).MATERIALS AND METHODS: We used least absolute shrinkage and selection operator to establish a prognostic score (PS) model based on the m5C regulator expression. Immune scores were calculated using the estimation of stromal and immune cells in malignant tumor tissues using expression data. The biological functions of the m5C regulator, NOP2/Sun RNA methyltransferase 3 (NSUN3), were thoroughly investigated in vitro and in vivo.
    RESULTS: The PS model acted as efficient prognostic factors in HNSCC. The expression of NSUN3, with the maximum weight, was found to be upregulated and indicated a poor prognosis. Meanwhile, NSUN3 knockdown inhibited the tumor proliferation and growth both in vitro and in vivo. High PS status was negatively correlated with CD8+ T, γδ+ T, and M1 macrophage percentages. NSUN3 knockdown increased the infiltration of M1 macrophages, but decreased the percentage of M2 macrophages.
    CONCLUSIONS: The PS index is a novel and promising biomarker for predicting the prognosis and immune infiltration microenvironment in HNSCC. Moreover, NSUN3 plays a key role in this process and may serve as a potential therapeutic target for HNSCC.
    Keywords:  5-methylcytosine; NSUN3; head and neck squamous cell carcinoma; immune infiltration; prognostic score
    DOI:  https://doi.org/10.1111/odi.14357
  30. Cancers (Basel). 2022 Aug 22. pii: 4056. [Epub ahead of print]14(16):
    The m6A-Related Long Noncoding RNA Signature Predicts Prognosis and Indicates Tumor Immune Infiltration in Ovarian Cancer.
    Rui Geng, Tian Chen, Zihang Zhong, Senmiao Ni, Jianling Bai, Jinhui Liu.
      Background: OV is the most lethal gynecological malignancy. M6A and lncRNAs have a great impact on OV development and patient immunotherapy response. In this paper, we decided to establish a reliable signature of mRLs. Method: The lncRNAs associated with m6A in OV were analyzed and obtained by co-expression analysis of the TCGA-OV database. Univariate, LASSO and multivariate Cox regression analyses were employed to establish the model of mRLs. K-M analysis, PCA, GSEA and nomogram based on the TCGA-OV and GEO database were conducted to prove the predictive value and independence of the model. The underlying relationship between the model and TME and cancer stemness properties were further investigated through immune feature comparison, consensus clustering analysis and pan-cancer analysis. Results: A prognostic signature comprising four mRLs, WAC-AS1, LINC00997, DNM3OS and FOXN3-AS1, was constructed and verified for OV according to the TCGA and GEO database. The expressions of the four mRLs were confirmed by qRT-PCR in clinical samples. Applying this signature, one can identify patients more effectively. The samples were divided into two clusters, and the clusters had different overall survival rates, clinical features and tumor microenvironments. Finally, pan-cancer analysis further demonstrated that the four mRLs were significantly related to immune infiltration, TME and cancer stemness properties in various cancer types. Conclusions: This study provided an accurate prognostic signature for patients with OV and elucidated the potential mechanism of the mRLs in immune modulation and treatment response, giving new insights into identifying new therapeutic targets.
    Keywords:  N6-methyladenosine; long noncoding RNAs; ovarian serous cystadenocarcinoma; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14164056
  31. Front Genet. 2022 ;13 934223
    YT521-B homology domain family proteins as N6-methyladenosine readers in tumors.
    Heng Yang, Chengyao Chiang, Qinhong Luo, Chunlan Chen, Junrong Huang, Lizhi Zhu, Duo Zheng.
      N6-methyladenosine (m6A) is the most abundant internal chemical modification of eukaryotic mRNA and plays diverse roles in gene regulation. The m6A modification plays a significant role in numerous cancer types, including kidney, stomach, lung, bladder tumors, and melanoma, through varied mechanisms. As direct m6A readers, the YT521-B homology domain family proteins (YTHDFs) play a key role in tumor transcription, translation, protein synthesis, tumor stemness, epithelial-mesenchymal transition (EMT), immune escape, and chemotherapy resistance. An in-depth understanding of the molecular mechanism of YTHDFs is expected to provide new strategies for tumor treatment. In this review, we provide a systematic description of YTHDF protein structure and its function in tumor progression.
    Keywords:  EMT; M6A; YTHDFs; chemotherapy resistance; immune escape; tumor
    DOI:  https://doi.org/10.3389/fgene.2022.934223
  32. STAR Protoc. 2022 Sep 16. 3(3): 101616
    Protocol for the generation of HIV-1 genomic RNA with altered levels of N 6-methyladenosine.
    Stacia Phillips, Alice Baek, Sanggu Kim, Shuliang Chen, Li Wu.
      N 6-methyladenosine (m6A) modification of human immunodeficiency virus type 1 (HIV-1) RNA plays a critical role in regulating viral replication and evasion of innate immunity. Here, we describe a protocol for the production of HIV-1 with altered m6A levels by manipulating the expression of m6A demethylases in HIV-1 producer cells. RNA from purified virions is analyzed by northern blot and dot blot for m6A levels prior to use in downstream assays to determine the function of m6A modification of viral RNA. For complete details on the use and execution of this protocol, please refer to Chen et al. (2021).
    Keywords:  Microbiology; Molecular biology
    DOI:  https://doi.org/10.1016/j.xpro.2022.101616
  33. Brief Bioinform. 2022 Aug 21. pii: bbac325. [Epub ahead of print]
    LRTCLS: low-rank tensor completion with Laplacian smoothing regularization for unveiling the post-transcriptional machinery of N6-methylation (m6A)-mediated diseases.
    Jiani Ma, Hui Liu, Yumeng Mao, Lin Zhang.
      Recently, N6-methylation (m6A) has recently become a hot topic due to its key role in disease pathogenesis. Identifying disease-related m6A sites aids in the understanding of the molecular mechanisms and biosynthetic pathways underlying m6A-mediated diseases. Existing methods treat it primarily as a binary classification issue, focusing solely on whether an m6A-disease association exists or not. Although they achieved good results, they all shared one common flaw: they ignored the post-transcriptional regulation events during disease pathogenesis, which makes biological interpretation unsatisfactory. Thus, accurate and explainable computational models are required to unveil the post-transcriptional regulation mechanisms of disease pathogenesis mediated by m6A modification, rather than simply inferring whether the m6A sites cause disease or not. Emerging laboratory experiments have revealed the interactions between m6A and other post-transcriptional regulation events, such as circular RNA (circRNA) targeting, microRNA (miRNA) targeting, RNA-binding protein binding and alternative splicing events, etc., present a diverse landscape during tumorigenesis. Based on these findings, we proposed a low-rank tensor completion-based method to infer disease-related m6A sites from a biological standpoint, which can further aid in specifying the post-transcriptional machinery of disease pathogenesis. It is so exciting that our biological analysis results show that Coronavirus disease 2019 may play a role in an m6A- and miRNA-dependent manner in inducing non-small cell lung cancer.
    Keywords:  Laplacian smoothing regularization term; Tucker decomposition; disease pathogenesis; m6A–event–disease association; multi-view learning; post-transcriptional events
    DOI:  https://doi.org/10.1093/bib/bbac325
  34. Front Oncol. 2022 ;12 929363
    Prognostic value of 12 m7G methylation-related miRNA markers and their correlation with immune infiltration in breast cancer.
    Wenchuan Zhang, Shuwan Zhang, Zhe Wang.
      RNA guanine-7 methyltransferase (RNMT), in complex with FAM103A1, plays an important role in tumorigenesis and development. The aim of this study was to establish a prognostic model of RNMT and FAM103A1-based upstream microRNAs and explore its correlation with immune cell infiltration in breast cancer (BC) while investigating its potential prognostic value and verify the model by quantitative real-time polymerase chain reaction (qRT-PCR). The miRNA expression data upstream of the m7G methyltransferase complex RNMT/FAM103A1 in BC was obtained from The Cancer Genome Atlas and TargetScan databases. We performed univariate Cox regression, LASSO regression, Kaplan-Meier survival, and principal component analyses, along with risk prognostic modelling. Based on multivariate Cox regression analysis, a total of 12 m7G methyltransferase-related miRNAs were found. The model showed good accuracy for predicting the 1-, 3-,5-, and 10-year survival rates, and the areas under the curve were almost >0.7. To characterize the risk-level model constructed from 12 miRNAs, 12 differentially expressed mRNAs related to prognosis and immune infiltration were obtained. The prognosis of BC patients is well predicted by the risk model we constructed. This model is also closely related to immune infiltration, and new immunotherapy targets can be explored from this field.
    Keywords:  FAM103A1; RNMT; breast cancer; immune infiltration; m7G; miRNA
    DOI:  https://doi.org/10.3389/fonc.2022.929363
  35. Biomolecules. 2022 Aug 17. pii: 1127. [Epub ahead of print]12(8):
    YTHDF3 Is Involved in the Diapause Process of Bivoltine Bombyx mori Strains by Regulating the Expression of Cyp307a1 and Cyp18a1 Genes in the Ecdysone Synthesis Pathway.
    Yanhua Chen, Bingyan Fan, Ayinuer Yasen, Juan Zhu, Meixian Wang, Xingjia Shen.
      The variable diapause features of bivoltine silkworm (Bombyx mori) strains regulated by environmental signals in the embryonic stage are closely related to epigenetics. Previously, we showed that the expression of YTHDF3 is significantly different in the pupae of the bivoltine silkworm Qiufeng developed from eggs incubated at a normal temperature (QFHT, diapause egg producer) compared to those from eggs incubated at a low temperature (QFLT, nondiapause egg producer), indicating that the expression of diapause-associated genes is regulated by the m6A modification level. However, how YTHDF3 regulates the expression of diapause-related genes remains unclear. In this study, we observed that the knockdown of B. mori YTHDF3 resulted in delayed embryo development, while the overexpression of YTHDF3 resulted in the transformation of nondiapause-destined eggs into a mixture of diapause and nondiapause eggs. Further studies showed that YTHDF3, as a reading protein, can recognize the m6A site of Cyp307a1 and Cyp18a1 genes in the ecdysone synthesis pathway (ESP), and the overexpression of YTHDF3 affects the diapause traits of the silkworm by decreasing the stabilities of mRNAs of Cyp307a1 and Cyp18a1 and inhibiting their translation. The above results demonstrate that m6A modification mediates YTHDF3 to affect the expression levels of its target genes, Cyp307a1 and Cyp18a1, in the ESP to regulate diapause in bivoltine B. mori. This is the first report of the m6A methylation regulation mechanism in diapause in B. mori and provides new experimental data for clarifying the diapause regulation network.
    Keywords:  Bombyx mori; Cyp18a1; Cyp307a1; RNA N6-methyladenosine; YTHDF3; diapause; mRNA stability; translation
    DOI:  https://doi.org/10.3390/biom12081127
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