bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2023–02–26
forty-one papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer.
  2. N6-methyladenosine modification in 18S rRNA promotes tumorigenesis and chemoresistance via HSF4b/HSP90B1/mutant p53 axis.
  3. Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication.
  4. MiR-141-3p promotes malignant progression in prostate cancer through AlkB homolog 5-mediated m6A modification of protein arginine methyltransferase 6.
  5. The Suppression Effects of Fat Mass and Obesity Associated Gene on the Hair Follicle-Derived Neural Crest Stem Cells Differentiating into Melanocyte by N6-Methyladenosine Modifying Microphthalmia-Associated Transcription Factor.
  6. Critical Roles of METTL3 in Translation Regulation of Cancer.
  7. ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells.
  8. Emerging roles of m6A RNA modification in cancer therapeutic resistance.
  9. A CRISPR-based Strategy for Temporally Controlled Site-Specific Editing of RNA Modifications.
  10. N6-methyladenosine methylation regulator FTO promotes oxidative stress and induces cell apoptosis in ovarian cancer.
  11. The Emerging Role of m6A Modification in Endocrine Cancer.
  12. RBM15 suppresses hepatic insulin sensitivity of offspring of gestational diabetes mellitus mice via m6A-mediated regulation of CLDN4.
  13. A Prognostic Signature for Colon Adenocarcinoma Patients Based on m6A-Related lncRNAs.
  14. m6A Modification-Association with Oxidative Stress and Implications on Eye Diseases.
  15. METTL14-dependent maturation of pri-miR-17 regulates mitochondrial homeostasis and induces chemoresistance in colorectal cancer.
  16. MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.
  17. The importance of m6A topology in chicken embryo mRNA; a precise mapping of m6A at the conserved chicken β-actin zipcode.
  18. HNRNPA2B1-Mediated MicroRNA-92a Upregulation and Section Acts as a Promising Noninvasive Diagnostic Biomarker in Colorectal Cancer.
  19. Evidence Based on an Integrative Analysis of Multi-Omics Data on METTL7A as a Molecular Marker in Pan-Cancer.
  20. Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy.
  21. Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages.
  22. The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection.
  23. RBM15 Promates the Proliferation, Migration and Invasion of Pancreatic Cancer Cell Lines.
  24. m6A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis.
  25. Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts.
  26. Molecular phenotypic linkage between N6-methyladenosine methylation and tumor immune microenvironment in hepatocellular carcinoma.
  27. m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization.
  28. The role of m6A-mediated PD-1/PD-L1 in antitumor immunity.
  29. RNA methyltransferase BmMettl3 and BmMettl14 in silkworm (Bombyx mori) and the regulation of silkworm embryonic development.
  30. N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2.
  31. The Epigenetic Regulation of RNA N6-Methyladenosine Methylation in Glycolipid Metabolism.
  32. A unique regulated cell death-related classification regarding prognosis and immune landscapes in non-small cell lung cancer.
  33. m6A mRNA modification promotes chilling tolerance and modulates gene translation efficiency in Arabidopsis.
  34. Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.
  35. M6A Promotes Colorectal Cancer Progression via Regulating the miR-27a-3p/BTG2 Pathway.
  36. Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.
  37. Disruption to tRNA modification by queuine contributes to inflammatory bowel disease.
  38. Redox Regulation of m 6 A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes.
  39. Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma.
  40. Comprehensive Pan-Cancer Analysis of KIF18A as a Marker for Prognosis and Immunity.
  41. Expression pattern and prognostic value of key regulators for N7-methylguanosine RNA modification in prostate cancer.
  1. Cancer Lett. 2023 Feb 15. pii: S0304-3835(23)00043-5. [Epub ahead of print]558 216092
    N6-methyadenosine modified SUV39H2 regulates homologous recombination through epigenetic repression of DUSP6 in gastric cancer.
    Jing Yang, Penghui Xu, Zetian Chen, Xing Zhang, Yiwen Xia, Lang Fang, Li Xie, Bowen Li, Zekuan Xu.
      Despite many advances in treatment over the past few years, the poor 5-year survival rate and high recurrence rate of gastric cancer (GC) remain unsatisfactory. As the most abundant epigenetic modification in the eukaryotic mRNA, N6-methyladenosine (m6A) methylation participates in tumor progression and tissue development. During tumor progression, DNA damage repair mechanisms can be reprogrammed to give new growth advantages on tumor clones whose genomic integrity is disturbed. Here we detected the elevated SUV39H2 expression in GC tissues and cell lines. Functionally, SUV39H2 promoted GC proliferation and inhibited apoptosis in vitro and in vivo. Mechanistically, METTL3-mediated m6A modification promotes mRNA stability of SUV39H2 in an IGF2BP2 dependent manner, resulting in upregulated mRNA expression of SUV39H2. As a histone methyltransferase, SUV39H2 was verified to increase the phosphorylation level of ATM through transcriptional repression of DUSP6, thereby promoting HRR and ultimately inhibiting GC chemosensitivity to cisplatin. Collectively, these results indicate the specific mechanism of m6A-modified SUV39H2 as a histone methyltransferase promoting HRR to inhibit the chemosensitivity of GC. SUV39H2 is expected to become a key target in the precision targeted therapy of GC.
    Keywords:  DSBs; Gastric cancer; Homologous recombination; SUV39H2; m(6)A modification
    DOI:  https://doi.org/10.1016/j.canlet.2023.216092
  2. Cell Chem Biol. 2023 Feb 16. pii: S2451-9456(23)00029-6. [Epub ahead of print]30(2): 144-158.e10
    N6-methyladenosine modification in 18S rRNA promotes tumorigenesis and chemoresistance via HSF4b/HSP90B1/mutant p53 axis.
    Binbin Chen, Ying Huang, Shuiqing He, Peng Yu, Lirong Wu, Hao Peng.
      Aberrant N6-methyladenosine (m6A) modification on mRNA is correlated with cancer progression. However, the role of m6A on ribosomal RNA (rRNA) in cancer remains poorly understood. Our current study reveals that METTL5/TRMT112 and their mediated m6A modification at the 18S rRNA 1832 site (m6A1832) are elevated in nasopharyngeal carcinoma (NPC) and promote oncogenic transformation in vitro and in vivo. Moreover, loss of catalytic activity of METTL5 abolishes its oncogenic functions. Mechanistically, m6A1832 18S rRNA modification facilitates the assembly of 80S ribosome via bridging the RPL24-18S rRNA interaction, therefore promoting the translation of mRNAs with 5' terminal oligopyrimidine (5' TOP) motifs. Further mechanistic analysis reveals that METTL5 enhances HSF4b translation to activate the transcription of HSP90B1, which binds with oncogenic mutant p53 (mutp53) protein and prevents it from undergoing ubiquitination-dependent degradation, therefore facilitating NPC tumorigenesis and chemoresistance. Overall, our findings uncover an innovative mechanism underlying rRNA epigenetic modification in regulating mRNA translation and the mutp53 pathway in cancer.
    Keywords:  18S rRNA; METTL5; m(6)A modification; mutant p53; nasopharyngeal carcinoma
    DOI:  https://doi.org/10.1016/j.chembiol.2023.01.006
  3. Front Microbiol. 2023 ;14 1087484
    Pseudorabies virus exploits N6-methyladenosine modification to promote viral replication.
    Pei-Lun Yu, Rui Wu, San-Jie Cao, Yi-Ping Wen, Xiao-Bo Huang, Shan Zhao, Yi-Fei Lang, Qin Zhao, Ju-Chun Lin, Sen-Yan Du, Shu-Min Yu, Qi-Gui Yan.
       Introduction: Pseudorabies virus (PRV) is the pathogenic virus of porcine pseudorabies (PR), belonging to the Herpesviridae family. PRV has a wide range of hosts and in recent years has also been reported to infect humans. N6-methyladenosine (m6A) modification is the major pathway of RNA post-transcriptional modification. Whether m6A modification participates in the regulation of PRV replication is unknown.
    Methods: Here, we investigated that the m6A modification was abundant in the PRV transcripts and PRV infection affected the epitranscriptome of host cells. Knockdown of cellular m6A methyltransferases METTL3 and METTL14 and the specific binding proteins YTHDF2 and YTHDF3 inhibited PRV replication, while silencing of demethylase ALKBH5 promoted PRV output. The overexpression of METTL14 induced more efficient virus proliferation in PRV-infected PK15 cells. Inhibition of m6A modification by 3-deazaadenosine (3-DAA), a m6A modification inhibitor, could significantly reduce viral replication.
    Results and Discussion: Taken together, m6A modification played a positive role in the regulation of PRV replication and gene expression. Our research revealed m6A modification sites in PRV transcripts and determined that m6A modification dynamically mediated the interaction between PRV and host.
    Keywords:  N6-methyladenosine; m6A regulators; pseudorabies virus; regulation; replication
    DOI:  https://doi.org/10.3389/fmicb.2023.1087484
  4. Chin J Physiol. 2023 Jan-Feb;66(1):66(1): 43-51
    MiR-141-3p promotes malignant progression in prostate cancer through AlkB homolog 5-mediated m6A modification of protein arginine methyltransferase 6.
    Xun Li, Bide Liu, Shuheng Wang, Jiuzhi Li, Xiaohu Ge.
      Prostate cancer (PCa) is one of the leading causes of cancer-related death in males worldwide and exploring more reliable biomarkers for PCa is essential for the diagnosis and therapeutics for the disease. Although the functions of miR-141-3p and AlkB homolog 5 (ALKBH5) were identified in some cancers, whether they were involved in the development of PCa remains unclear. In this study, reverse transcription-quantitative polymerase chain reaction unveiled that the expression of ALKBH5 was reduced in PCa tissues and was negatively correlated with miR-141-3p. ALKBH5 attenuated the malignant development of PCa through suppressing the growth, migration, invasion, and sphere formation abilities of PCa cells. In addition, the luciferase activity assay identified that ALKBH5 was corroborated as a downstream target of miR-141-3p. Moreover, miR-141-3p expression was boosted in PCa tissues and cells and inhibition of miR-141-3p suppressed the tumor growth of PCa in vivo. Moreover, ALKBH5 was confirmed to suppress protein arginine methyltransferase 6 (PRMT6) expression through N6-methyladenosine (m6A) modification. We further identified that miR-141-3p-modulated PRMT6 level through mediating ALKBH5. Furthermore, PRMT6 level was positively correlated with miR-141-3p level and negatively associated with ALKBH5 level. Finally, rescue assays also uncovered that miR-141-3p aggravated PCa development by regulating PRMT6. In conclusion, miR-141-3p accelerated the malignant progression of PCa through ALKBH5-mediated m6A modification of PRMT6, which might offer a novel insight into the role of miR-141-3p and ALKBH5 in the treatments of PCa patients.
    Keywords:  AlkB homolog 5; m6A; miR-141-3p; prostate cancer; protein arginine methyltransferase 6
    DOI:  https://doi.org/10.4103/cjop.CJOP-D-22-00071
  5. Int J Stem Cells. 2023 Feb 28.
    The Suppression Effects of Fat Mass and Obesity Associated Gene on the Hair Follicle-Derived Neural Crest Stem Cells Differentiating into Melanocyte by N6-Methyladenosine Modifying Microphthalmia-Associated Transcription Factor.
    Zhiwei Shang, Haixia Feng, Liye Xia.
       Background and Objectives: Melanocyte (MC), derived from neural crest stem cell (NCSC), are involved in the production of melanin. The mechanism by which NCSC differentiates to MC remains unclear. N6-methyladenosine (m6A) modification was applied to discuss the potential mechanism.
    Methods and Results: NCSCs were isolated from hair follicles of rats, and were obtained for differentiation. Cell viability, tyrosinase secretion and activity, and transcription factors were combined to evaluated the MC differentiation. RT-qPCR was applied to determine mRNA levels, and western blot were used for protein expression detection. Total m6A level was measured using methylated RNA immunoprecipitation (MeRIP) assay, and RNA immunoprecipitation was used to access the protein binding relationship. In current work, NCSCs were successfully differentiated into MCs. Fat mass and obesity associated gene (FTO) was aberrant downregulated in MCs, and elevated FTO suppressed the differentiation progress of NCSCs into MCs. Furthermore, microphthalmia-associated transcription factor (Mitf), a key gene involved in MC synthesis, was enriched by FTO in a m6A modification manner and degraded by FTO. Meanwhile, the suppression functions of FTO in the differentiation of NCSCs into MCs were reversed by elevated Mitf.
    Conclusions: In short, FTO suppressed the differentiating ability of hair follicle-derived NCSCs into MCs by m6A modifying Mitf.
    Keywords:  Differentiation; FTO; Melanocyte; Mitf; N6-methyladenosine; Neural crest stem cell
    DOI:  https://doi.org/10.15283/ijsc22106
  6. Biomolecules. 2023 Jan 27. pii: 243. [Epub ahead of print]13(2):
    Critical Roles of METTL3 in Translation Regulation of Cancer.
    Wangyang Meng, Han Xiao, Peiyuan Mei, Jiaping Chen, Yangwei Wang, Rong Zhao, Yongde Liao.
      Aberrant translation, a characteristic feature of cancer, is regulated by the complex and sophisticated RNA binding proteins (RBPs) in the canonical translation machinery. N6-methyladenosine (m6A) modifications are the most abundant internal modifications in mRNAs mediated by methyltransferase-like 3 (METTL3). METTL3 is commonly aberrantly expressed in different tumors and affects the mRNA translation of many oncogenes or dysregulated tumor suppressor genes in a variety of ways. In this review, we discuss the critical roles of METTL3 in translation regulation and how METTL3 and m6A reader proteins in collaboration with RBPs within the canonical translation machinery promote aberrant translation in tumorigenesis, providing an overview of recent efforts aiming to 'translate' these results to the clinic.
    Keywords:  METTL3; RNA binding protein; cancer; eukaryotic initiation factor; m6A; post-transcriptional modification; translation regulation
    DOI:  https://doi.org/10.3390/biom13020243
  7. Clin Transl Oncol. 2023 Feb 23.
    ALKBH5 decreases SLC7A11 expression by erasing m6A modification and promotes the ferroptosis of colorectal cancer cells.
    Jing Luo, Hongmei Yu, Zhen Yuan, Tao Ye, Bo Hu.
       BACKGROUND: Colorectal cancer (CRC) is the major subtype of gastrointestinal malignancy and involves cancer-related genes and signaling pathways to regulate ferroptosis. The present study was conducted to analyze the role of alkB homolog 5 (ALKBH5) in the ferroptosis of CRC cells and provide novel targets for CRC treatment.
    METHODS: The transcriptional and protein levels of ALKBH5 and solute carrier family 7 members 11 (SLC7A11) in tissues and cells were determined by qRT-PCR and Western blot assay. HCT116 and SW620 cells were transfected with ALKBH5 overexpression vectors to determine cell viability and levels of reactive oxygen species (ROS), Fe+, glutathione, and glutathione peroxidase 4 using cell counting kit-8, colony formation, fluorescence probe, assay kits, and Western blot assay. The N6-methyladenosine (m6A) level and the enrichment of m6A on SLC7A11 mRNA were measured by m6A quantitative analysis and m6A methylated RNA immunoprecipitation-qPCR, and the mRNA stability was determined after actinomycin D treatment. CRC cells were treated with the combination of SLC7A11 and ALKBH5 overexpression vectors to confirm the mechanism. Nude mice were subcutaneously injected with CRC cells overexpressing ALKBH5.
    RESULTS: ALKBH5 was downregulated in CRC and ALKBH5 overexpression promoted ROS release and ferroptosis. ALKBH5 erased the m6A modification on SLC7A11 mRNA to reduce the mRNA stability of SLC7A11, further reducing SLC7A11 expression. SLC7A11 overexpression reversed the promotive role of ALKBH5 overexpression in ferroptosis. ALKBH5 upregulation mitigated tumor growth in vivo.
    CONCLUSIONS: ALKBH5 reduced SLC7A11 transcription by erasing m6A modification, thus promoting the ferroptosis of CRC cells.
    Keywords:  ALKBH5; Colorectal cancer; Ferroptosis; SLC7A11; m6A modification
    DOI:  https://doi.org/10.1007/s12094-023-03116-6
  8. Exp Hematol Oncol. 2023 Feb 21. 12(1): 21
    Emerging roles of m6A RNA modification in cancer therapeutic resistance.
    Wei-Wei Liu, Zhong-Yuan Zhang, Fei Wang, Hao Wang.
      Marvelous advancements have been made in cancer therapies to improve clinical outcomes over the years. However, therapeutic resistance has always been a major difficulty in cancer therapy, with extremely complicated mechanisms remain elusive. N6-methyladenosine (m6A) RNA modification, a hotspot in epigenetics, has gained growing attention as a potential determinant of therapeutic resistance. As the most prevalent RNA modification, m6A is involved in every links of RNA metabolism, including RNA splicing, nuclear export, translation and stability. Three kinds of regulators, "writer" (methyltransferase), "eraser" (demethylase) and "reader" (m6A binding proteins), together orchestrate the dynamic and reversible process of m6A modification. Herein, we primarily reviewed the regulatory mechanisms of m6A in therapeutic resistance, including chemotherapy, targeted therapy, radiotherapy and immunotherapy. Then we discussed the clinical potential of m6A modification to overcome resistance and optimize cancer therapy. Additionally, we proposed existing problems in current research and prospects for future research.
    Keywords:  Cancer therapy; Chemoresistance; Immunotherapy; m6A
    DOI:  https://doi.org/10.1186/s40164-023-00386-2
  9. Bio Protoc. 2023 Feb 05. 13(3): e4607
    A CRISPR-based Strategy for Temporally Controlled Site-Specific Editing of RNA Modifications.
    Ying Xu, Yufan Wang, Fu-Sen Liang.
      Chemical modifications on RNA play important roles in regulating its fate and various biological activities. However, the impact of RNA modifications varies depending on their locations on different transcripts and cells/tissues contexts; available tools to dissect context-specific RNA modifications are still limited. Herein, we report the detailed protocol for using a chemically inducible and reversible platform to achieve site-specific editing of the chosen RNA modification in a temporally controlled manner by integrating the clustered regularly interspaced short palindromic repeats (CRISPR) technology and the abscisic acid (ABA)-based chemically induced proximity (CIP) system. The procedures were demonstrated using the example of inducible and reversible N6-methyladenosine (m6A) editing and the evaluation of its impact on RNA properties with ABA addition and reversal with the control of ABA or light.
    Keywords:  Abscisic acid; CRISPR; Chemically induced proximity; RNA modification; Temporal control; m6A
    DOI:  https://doi.org/10.21769/BioProtoc.4607
  10. Epigenomics. 2023 Feb 22.
    N6-methyladenosine methylation regulator FTO promotes oxidative stress and induces cell apoptosis in ovarian cancer.
    Jun Wu, Xiaoqin Wang, Xin Li.
      Aims: This study aimed to reveal the possible molecular mechanism of n6-methyladenosine (m6A) methylation regulator FTO in the biological activities of ovarian cancer (OC) based on The Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases. Materials & methods: A risk score model was constructed to predict the prognosis of patients with OC. The key m6A methylation regulator was screened out based on OC-related microarray datasets. Results: 22 m6A methylation regulators were differentially expressed and interacted with each other in OC. FTO, a key m6A methylation regulator, was singled out. In vivo experiments verified that FTO promoted oxidative stress and apoptosis of OC cells to inhibit tumor growth in nude mice. Conclusion: This study highlighted the tumor-suppressive mechanism of m6A methylation regulator FTO in OC.
    Keywords:  FTO; P53 signaling pathway; m6A methylation regulator; ovarian cancer; oxidative stress
    DOI:  https://doi.org/10.2217/epi-2022-0403
  11. Cancers (Basel). 2023 Feb 06. pii: 1033. [Epub ahead of print]15(4):
    The Emerging Role of m6A Modification in Endocrine Cancer.
    Xiaoyu Ji, Zhiyuan Wang, Wei Sun, Hao Zhang.
      With the development of RNA modification research, N6-methyladenosine (m6A) is regarded as one of the most important internal epigenetic modifications of eukaryotic mRNA. It is also regulated by methylase, demethylase, and protein preferentially recognizing the m6A modification. This dynamic and reversible post-transcriptional RNA alteration has steadily become the focus of cancer research. It can increase tumor stem cell self-renewal and cell proliferation. The m6A-modified genes may be the primary focus for cancer breakthroughs. Although some endocrine cancers are rare, they may have a high mortality rate. As a result, it is critical to recognize the significance of endocrine cancers and identify new therapeutic targets that will aid in improving disease treatment and prognosis. We summarized the latest experimental progress in the m6A modification in endocrine cancers and proposed the m6A alteration as a potential diagnostic marker for endocrine malignancies.
    Keywords:  demethylase; endocrine cancer; m6A; methyltransferase
    DOI:  https://doi.org/10.3390/cancers15041033
  12. Mol Med. 2023 Feb 20. 29(1): 23
    RBM15 suppresses hepatic insulin sensitivity of offspring of gestational diabetes mellitus mice via m6A-mediated regulation of CLDN4.
    Jie Fang, Xiafei Wu, Jie He, Hanwen Zhang, Xuyang Chen, Hua Zhang, Boris Novakovic, Hongbo Qi, Xinyang Yu.
       BACKGROUND: Gestational diabetes Mellitus (GDM) is a common pregnancy-specific disease with high morbidity, which is linked to a high risk of obesity and diabetes in offspring. N6-methyladenosine modification of RNA is emerging as an important epigenetic mechanism that is widely manifested in many diseases. This study aimed to investigate the mechanism of m6A methylation in metabolic syndrome in offspring result from intrauterine hyperglycemia.
    METHODS: GDM mice were established by feeding a high-fat diet 1 weeks before pregnancy. The m6A RNA methylation quantification kit was used to detect liver tissue methylation levels. PCR array was used to determine the expression of the m6A methylation modification enzyme. Immunohistochemistry, qRT-PCR, and western blot were used to examine the expression of RBM15, METTL13, IGF2BP1, and IGF2BP2. Subsequently, methylated RNA immunoprecipitation sequencing combined with mRNA sequencing, followed by dot blot and glucose uptake tests, were performed.
    RESULTS: In this study, we found that offspring from a GDM mother were more vulnerable to glucose intolerance and insulin resistance. GC-MS revealed significant metabolic changes including saturated fatty acids and unsaturated fatty acids in liver of GDM offspring. We also demonstrated that global mRNA m6A methylation level was significantly increased in the fetal liver of GDM mice, indicating epigenetic change may have a strong relationship with the mechanism of metabolism syndrome. Concordantly, RBM15, the RNA binding methyltransferase, was upregulated in the liver. In vitro, RBM15 suppressed insulin sensitivity and increased insulin resistance through m6A-regulated epigenetic inhabitation of CLDN4. Moreover, MeRIP-sequencing and mRNA-sequencing revealed that differently regulated genes with differential m6A peaks were enriched in metabolic pathways.
    CONCLUSION: Our study revealed the essential role of RBM15 in insulin resistance and the effect of RBM15-regulated m6A modification in the metabolic syndrome of offspring of GDM mice.
    Keywords:  CLDN4; Gestational diabetes mellitus (GDM); Metabolic syndrome; N6-methyladenosine (m6A); RBM15; RNA modifications
    DOI:  https://doi.org/10.1186/s10020-023-00615-8
  13. J Oncol. 2023 ;2023 7797710
    A Prognostic Signature for Colon Adenocarcinoma Patients Based on m6A-Related lncRNAs.
    Su-Zhe Zhou, Ying-Lian Pan, Qing-Chun Deng, Chang-Jun Yin, De-Jiang Zhou, Ming-Liang Liu, Jun Zhou, Xiao-Jing Wu.
      N6-methyladenosine (m6A) modification is a common epigenetic modification. It is reported that lncRNA can be regulated by m6A modification. Previous studies have shown that lncRNAs associated with m6A regulation (m6A-lncRNAs) serve as ideal prognostic biomarkers. However, whether lncRNAs are involved in m6A modification in colon adenocarcinoma (COAD) needs further exploration. The objective of this study was to construct an m6A-lncRNAs-based signature for patients with COAD. We obtained the RNA sequencing data and clinical information from The Cancer Genome Atlas (TCGA). Pearson correlation analysis was employed to recognize lncRNAs associated with m6A regulation (m6A-lncRNAs). 24 prognostic m6A-lncRNAs was identified by univariate Cox regression analysis. Gene set enrichment analysis (GSAE) was used to investigate the potential cellular pathways and biological processes. We have also explored the relationship between immune infiltrate levels and m6A-lncRNAs. Then, a predictive signature based on the expression of 13 m6A-lncRNAs was constructed by the Lasso regression algorithm, including UBA6-AS1, AC139149.1, U91328.1, AC138207.5, AC025171.4, AC008760.1, ITGB1-DT, AP001619.1, AL391422.4, AC104532.2, ZEB1-AS1, AC156455.1, and AC104819.3. ROC curves and K M survival curves have shown that the risk score has a well-predictive ability. We also set up a quantitative nomogram on the basis of risk score and prognosis-related clinical characteristics. In summary, we have identified some m6A-lncRNAs that correlated with prognosis and tumor immune microenvironment in COAD. In addition, a potential alternative signature based on the expression of m6A-lncRNAs was provided for the management of COAD patients.
    DOI:  https://doi.org/10.1155/2023/7797710
  14. Antioxidants (Basel). 2023 Feb 17. pii: 510. [Epub ahead of print]12(2):
    m6A Modification-Association with Oxidative Stress and Implications on Eye Diseases.
    Yueqi Ni, Hong Zhang, Liang Chu, Yin Zhao.
      Oxidative stress (OS) refers to a state of imbalance between oxidation and antioxidation. OS is considered to be an important factor leading to aging and a range of diseases. The eyes are highly oxygen-consuming organs. Due to its continuous exposure to ultraviolet light, the eye is particularly vulnerable to the impact of OS, leading to eye diseases such as corneal disease, cataracts, glaucoma, etc. The N6-methyladenosine (m6A) modification is the most investigated RNA post-transcriptional modification and participates in a variety of cellular biological processes. In this study, we review the role of m6A modification in oxidative stress-induced eye diseases and some therapeutic methods to provide a relatively overall understanding of m6A modification in oxidative stress-related eye diseases.
    Keywords:  eye diseases; m6A modification; oxidative stress; treatment
    DOI:  https://doi.org/10.3390/antiox12020510
  15. Cell Death Dis. 2023 Feb 21. 14(2): 148
    METTL14-dependent maturation of pri-miR-17 regulates mitochondrial homeostasis and induces chemoresistance in colorectal cancer.
    Kangyue Sun, Lu Chen, Yiwen Li, Bing Huang, Qun Yan, Changjie Wu, Qiuhua Lai, Yuxin Fang, Jianqun Cai, Yongfeng Liu, Junsheng Chen, Xinke Wang, Yuxuan Zhu, Shuyu Dong, Jieyu Tan, Aimin Li, Side Liu, Yue Zhang.
      miR-17-5p has been found to be involved in the proliferation and metastasis of colorectal cancer (CRC), and N6-methyladenosine (m6A) modification is the most common RNA modification in eukaryotes. However, whether miR-17-5p contributes to chemotherapy sensitivity in CRC via m6A modification is unclear. In this study, we found that overexpression of miR-17-5p led to less apoptosis and lower drug sensitivity in vitro and in vivo under the 5-fluorouracil (5-FU) treatment, which indicated miR-17-5p led to 5-FU chemotherapy resistance. Bioinformatic analysis suggested that miR-17-5p-mediated chemoresistance was associated with mitochondrial homeostasis. miR-17-5p directly bound to the 3' untranslated region of Mitofusin 2 (MFN2), leading to decreased mitochondrial fusion and enhanced mitochondrial fission and mitophagy. Meanwhile, methyltransferase-like protein 14 (METTL14) was downregulated in CRC, resulting in lower m6A level. Moreover, the low level of METTL14 promoted the expression of pri-miR-17 and miR-17-5p. Further experiments suggested that m6A mRNA methylation initiated by METTL14 inhibits pri-miR-17 mRNA decay via reducing the recognition of YTHDC2 to the "GGACC" binding site. The METTL14/miR-17-5p/MFN2 signaling axis may play a critical role in 5-FU chemoresistance in CRC.
    DOI:  https://doi.org/10.1038/s41419-023-05670-x
  16. Acta Biochim Pol. 2023 Feb 22.
    MALAT-1 regulates the AML progression by promoting the m6A modification of ZEB1.
    Jing Jin, Leihua Fu, Pan Hong, Weiying Feng.
      Metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) is abnormally upregulated in various human cancers. However, the role of MALAT-1 in acute myeloid leukemia (AML) remains unclear. This study investigated the expression and function of MALAT-1 in AML. MTT assay was used to determine cell viability, qRT-PCR was applied to determine the RNA levels. Western blot was performed to detect the protein expression. Flow cytometry was conducted to measure cell apoptosis. RNA pull-down assay was carried out to detect the interaction between MALAT-1 and METTL14. RNA FISH assay was performed to determine the localization of MALAT-1 and METTL14 in AML cells. Our results have revealed the key role of MEEL14 and m6A modification in AML. Besides, MALAT-1 was significantly up-regulated in AML patients. MALAT-1 knockdown inhibited the proliferation, migration and invasion of AML cells, and induced cell apoptosis; additionally, MALAT-1 binding to METTL14 promoted the m6A modification of ZEB1. Besides, ZEB1 overexpression partially reversed the effect of MALAT-1 knockdown on the cellular functions of AML cells. Taken together, MALAT-1 promoted the aggressiveness of AML through regulating m6A modification of ZEB1.
    DOI:  https://doi.org/10.18388/abp.2020_6017
  17. RNA. 2023 Feb 21. pii: rna.079615.123. [Epub ahead of print]
    The importance of m6A topology in chicken embryo mRNA; a precise mapping of m6A at the conserved chicken β-actin zipcode.
    Francis Baron, Mi Zhang, Nathan Archer, Eleanor Bellows, Helen M Knight, Simon Welham, Catrin S Rutland, Nigel P Mongan, Chris J Hayes, Rupert Fray, Zsuzsa Bodi.
      N6-Methyladenosine (m6A) in mRNA regulates almost every stage in the mRNA life cycle, and the development of methodologies for the high throughput detection of methylated sites in mRNA using m6A-specific methylated RNA immunoprecipitation with next-generation sequencing (MeRIPSeq) or m6A individual-nucleotide-resolution cross-linking and immunoprecipitation (miCLIP) have revolutionized the m6A research field. Both of these methods are based on immunoprecipitation of fragmented mRNA. However, it is well documented that antibodies often have nonspecific activities, thus verification of identified m6A sites using an antibody-independent method would be highly desirable. We mapped and quantified the m6A site in the chicken β-actin zipcode based on the data from chicken embryo MeRIPSeq results and our RNA-Epimodification Detection and Base-Recognition (RedBaron) antibody independent assay. We also demonstrated that methylation of this site in the β-actin zipcode enhances ZBP1 binding in vitro, whilst methylation of a nearby adenosine abolishes binding. This suggests that m6A may play a role in regulating localised translation of β-actin mRNA, and the ability of m6A to enhance or inhibit a reader protein's RNA binding highlights the importance of m6A detection at nucleotide resolution.
    Keywords:  β-actin localization; MeRIPSeq; RedBaron method; m6A site specific quantification; m6A site verification
    DOI:  https://doi.org/10.1261/rna.079615.123
  18. Cancers (Basel). 2023 Feb 21. pii: 1367. [Epub ahead of print]15(4):
    HNRNPA2B1-Mediated MicroRNA-92a Upregulation and Section Acts as a Promising Noninvasive Diagnostic Biomarker in Colorectal Cancer.
    Yiling Li, Kexin Li, Xiaoying Lou, Yue Wu, Samuel Seery, Danfei Xu, Yuqing Pei, Benheng Qian, Yuxin Wu, Shuang Liang, Kui Wu, Wei Cui.
      MicroRNA-92a (miR-92a) may serve as a novel promising biomarker in multiple cancers, including colorectal cancer (CRC); however, the diagnostic accuracy and the underlying molecular mechanism of miR-92a in CRC is poorly understood. We first carried out meta-analysis and found that serum/plasma miR-92a yield better diagnostic efficacy when compared to stool samples and CRC tissues, and this finding was validated by our independent study through stool sample. Multiple bioinformatics assay indicated that miR-92a expression was positively correlated with heterogeneous nuclear ribonucleoproteins A2/B1 (HNRNPA2B1) expression and closely related with the clinical characteristics of CRC. Experimental evidence showed that knockdown of HNRNPA2B1 could significantly decrease miR-92a expression and secretion in RKO cells. HNRNPA2B1 mediated miR-92a via m6A RNA modification. These findings indicate that HNRNPA2B1-m6A RNA modification-derived MicroRNA-92a upregulation and section from the local CRC acts a candidate noninvasive serum biomarker in colorectal cancer. Our study provides a novel insight into miR-92a mechanisms in relation to both expression and secretion for CRC diagnosis.
    Keywords:  N6-methyladenosine (m6A); biomarker; colorectal cancer; hnRNPA2B1; miR-92a
    DOI:  https://doi.org/10.3390/cancers15051367
  19. Biomolecules. 2023 Jan 18. pii: 195. [Epub ahead of print]13(2):
    Evidence Based on an Integrative Analysis of Multi-Omics Data on METTL7A as a Molecular Marker in Pan-Cancer.
    Zikai Liu, Yiqun Chen, Tong Shen.
      Methyltransferase-like protein 7A (METTL7A), an RNA N6-methyladenosine (m6A) methyltransferase, has attracted much attention as it has been found to be closely associated with various types of tumorigenesis and progression. This study provides a comprehensive assessment of METTL7A from a pan-cancer perspective using multi-omics data. The gene ontology enrichment analysis of METTL7A-binding proteins revealed a close association with methylation and lipid metabolism. We then explored the expression of METTL7A in normal tissues, cell lines, different subtypes and cancers, and found that METTL7A was differentially expressed in various cancer species, tumor molecular subtypes and immune subtypes. Evaluation of the diagnostic and prognostic value of METTL7A in pan-cancer revealed that METTL7A had high accuracy in tumor prediction. Moreover, the low expression of METTL7A significantly correlated with the poor prognosis, including kidney renal clear cell carcinoma (KIRC), mesothelioma and sarcoma, indicating that METTL7A could be a potential biomarker for tumor diagnosis and prognosis. We focused on KIRC after pre-screening and analyzed its expression and prognostic value in various clinical subgroups. We found that METTL7A was significantly related to tumor stage, metastasis stage, pathologic stage, primary therapy outcome, histologic grade and gender, and that low METTL7A expression was associated with poorer outcomes. Finally, we analyzed the immune infiltration and co-expressed genes of METTL7A as well as the differentially expressed genes in the high and low expression groups. In conclusion, METTL7A is a better molecular marker for pan-cancer diagnosis and prognosis and has high potential as a diagnostic and prognostic biomarker for KIRC.
    Keywords:  METTL7A; biomarker; omics integrative analysis; pan-cancer analysis
    DOI:  https://doi.org/10.3390/biom13020195
  20. Mol Cancer. 2023 Feb 21. 22(1): 36
    Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy.
    Xianyong Zhou, Chen Li, Tong Chen, Wenhao Li, Xiaolong Wang, Qifeng Yang.
      Cancer immunotherapy, especially immune checkpoint therapy, has revolutionized therapeutic options by reactivating the host immune system. However, the efficacy varies, and only a small portion of patients develop sustained antitumor responses. Hence, illustrating novel strategies that improve the clinical outcome of immune checkpoint therapy is urgently needed. N6-methyladenosine (m6A) has been proved to be an efficient and dynamic posttranscriptional modification process. It is involved in numerous RNA processing, such as splicing, trafficking, translation and degradation. Compelling evidence emphasizes the paramount role of m6A modification in the regulation of immune response. These findings may provide a foundation for the rational combination of targeting m6A modification and immune checkpoints in cancer treatment. In the present review, we summarize the current landscape of m6A modification in RNA biology, and highlight the latest findings on the complex mechanisms by which m6A modification governs immune checkpoint molecules. Furthermore, given the critical role of m6A modification in antitumor immunity, we discuss the clinical significance of targeting m6A modification to improve the efficacy of immune checkpoint therapy for cancer control.
    Keywords:  Cancer immunotherapy; Epigenetics; Immune checkpoint; N6-methyladenosine; m6A regulators
    DOI:  https://doi.org/10.1186/s12943-023-01746-6
  21. Redox Biol. 2023 Feb 15. pii: S2213-2317(23)00039-3. [Epub ahead of print]61 102638
    Ythdf2 promotes pulmonary hypertension by suppressing Hmox1-dependent anti-inflammatory and antioxidant function in alveolar macrophages.
    Li Hu, Yanfang Yu, Yueyao Shen, Huijie Huang, Donghai Lin, Kang Wang, Youjia Yu, Kai Li, Yue Cao, Qiang Wang, Xiaoxuan Sun, Zhibing Qiu, Dong Wei, Bin Shen, Jingyu Chen, David Fulton, Yong Ji, Jie Wang, Feng Chen.
      Pulmonary hypertension (PH) is a devastating disease characterized by irreversible pulmonary vascular remodeling (PVR) that causes right ventricular failure and death. The early alternative activation of macrophages is a critical event in the development of PVR and PH, but the underlying mechanisms remain elusive. Previously we have shown that N6-methyladenosine (m6A) modifications of RNA contribute to phenotypic switching of pulmonary artery smooth muscle cells and PH. In the current study, we identify Ythdf2, an m6A reader, as an important regulator of pulmonary inflammation and redox regulation in PH. In a mouse model of PH, the protein expression of Ythdf2 was increased in alveolar macrophages (AMs) during the early stages of hypoxia. Mice with a myeloid specific knockout of Ythdf2 (Ythdf2Lyz2 Cre) were protected from PH with attenuated right ventricular hypertrophy and PVR compared to control mice and this was accompanied by decreased macrophage polarization and oxidative stress. In the absence of Ythdf2, heme oxygenase 1 (Hmox1) mRNA and protein expression were significantly elevated in hypoxic AMs. Mechanistically, Ythdf2 promoted the degradation of Hmox1 mRNA in a m6A dependent manner. Furthermore, an inhibitor of Hmox1 promoted macrophage alternative activation, and reversed the protection from PH seen in Ythdf2Lyz2 Cre mice under hypoxic exposure. Together, our data reveal a novel mechanism linking m6A RNA modification with changes in macrophage phenotype, inflammation and oxidative stress in PH, and identify Hmox1 as a downstream target of Ythdf2, suggesting that Ythdf2 may be a therapeutic target in PH.
    Keywords:  Alveolar macrophages; Heme oxygenase 1; Inflammation; Oxidant stress; Pulmonary hypertension; Ythdf2
    DOI:  https://doi.org/10.1016/j.redox.2023.102638
  22. Oxid Med Cell Longev. 2023 ;2023 3918393
    The Effect of N6-Methyladenosine Regulators and m6A Reader YTHDC1-Mediated N6-Methyladenosine Modification Is Involved in Oxidative Stress in Human Aortic Dissection.
    Fanxing Yin, Kun Liu, Wanfu Peng, Deying Jiang, Hao Zhang, Panpan Guo, Yinhao Wu, Xiaoxu Zhang, Chenxi Sun, Yaxuan Wang, Hecheng Wang, Yanshuo Han.
      Aortic dissection (AD) develops pathological changes in the separation of the true and false aortic lumen, with high lethality. m6A methylation and oxidative stress have also been shown to be involved in the onset of AD. Through bioinformatics methods, three differentially expressed m6A regulators (YTHDC1, YTHDC2, and RBM15) were excavated from the GSE52093 dataset in the Gene Expression Omnibus (GEO) database, and functional enrichment analysis of the differentially expressed genes (DEGs) regulated by m6A regulators was performed. Then, the genes with oxidative stress-related functions among these genes were found. The protein interaction network of the oxidative stress-related genes and the competing endogenous RNA- (ceRNA-) miRNA-mRNA network were constructed. Among them, DHCR24, P4HB, and PDGFRA, which have m6A differences in AD samples, were selected as key genes. We also performed immune infiltration analysis, as well as cell-gene correlation analysis, on samples from the dataset. The results showed that YTHDC1 was positively correlated with macrophage M1 and negatively correlated with macrophage M2. Finally, we extracted AD and healthy aorta RNA and protein from human tissues that were taken from AD patients and patients who received heart transplants, performed quantitative real-time PCR (qRT-PCR) on YTHDC2 and RBM15, and performed qRT-PCR and western blot (WB) detection on YTHDC1 to verify their differences in AD. The mRNA and protein levels of YTHDC1 were consistent with the results of bioinformatics analysis and were downregulated in AD. Immunofluorescence (IF) was used to colocalize YTHDC1 and endothelial cell marker CD31. After knocking down YTHDC1 in human umbilical vein endothelial cells (HUVECs), reactive oxygen species (ROS) levels had a tendency to increase and the expression of peroxide dismutase SOD2 was decreased. This study provides assistance in discovering the role of m6A regulator YTHDC1 in AD. In particular, m6A modification participates in oxidative stress and jointly affects AD.
    DOI:  https://doi.org/10.1155/2023/3918393
  23. Cancers (Basel). 2023 Feb 08. pii: 1084. [Epub ahead of print]15(4):
    RBM15 Promates the Proliferation, Migration and Invasion of Pancreatic Cancer Cell Lines.
    Hui Dong, Haidong Zhang, Xinyu Mao, Shiwei Liu, Wenjing Xu, Yewei Zhang.
      (1) Background: Pancreatic cancer is increasingly becoming the leading cause of cancer deaths worldwide. In eukaryotic cells, m6A is the most abundant mRNA methylation modification. (2) Methods: We performed a bioinformatic multidimensional analysis using files containing the clinical data of patients and m6A-related gene expression differences downloaded from web-based databases, and performed a statistical analysis and image mapping mainly using R-package. Next, we studied the RBM15 expression in cancer and paracancerous tissues. We then validated these findings in two cell lines by western blot, PCR, Transwell, CCK-8, and EDU animal models. (3) Results: We discovered that RBM15 was highly expressed in pancreatic cancer patients and that it is a significant cause of poor prognosis. Its association with lymphatic T cell family aggregation was established through immune infiltration analysis. A retrospective analysis of data from clinical patient specimens revealed that high expression of RBM15 in patients was closely and positively correlated with preoperative glucose values, gender, and lymphocyte counts. Results from cellular experiments and animal experiments indicated that when the RBM15 gene was silenced, cell proliferation, migration, and metastasis were inhibited. (4) Conclusions: We propose that RBM15 plays a key role in the progression of pancreatic cancer by promoting tumor proliferation, migration and metastasis.
    Keywords:  RBM15; m6A; pancreatic cancer; pancreatic cancer cell lines
    DOI:  https://doi.org/10.3390/cancers15041084
  24. Pharmacol Res. 2023 Feb 20. pii: S1043-6618(23)00060-9. [Epub ahead of print]189 106704
    m6A methylation-induced NR1D1 ablation disrupts the HSC circadian clock and promotes hepatic fibrosis.
    Li Chen, Siwei Xia, Feixia Wang, Yuanyuan Zhou, Shuqi Wang, Ting Yang, Yang Li, Min Xu, Ya Zhou, Desong Kong, Zili Zhang, Jiangjuan Shao, Xuefen Xu, Feng Zhang, Shizhong Zheng.
      The roles of nuclear receptor subfamily 1 group d member 1 (NR1D1) and the circadian clock in liver fibrosis remain unclear. Here, we showed that liver clock genes, especially NR1D1, were dysregulated in mice with carbon tetrachloride (CCl4)-induced liver fibrosis. In turn, disruption of the circadian clock exacerbated experimental liver fibrosis. NR1D1-deficient mice were more sensitive to CCl4-induced liver fibrosis, supporting a critical role of NR1D1 in liver fibrosis development. Validation at the tissue and cellular levels showed that NR1D1 was primarily degraded by N6-methyladenosine (m6A) methylation in a CCl4-induced liver fibrosis model, and this result was also validated in rhythm-disordered mouse models. In addition, the degradation of NR1D1 further inhibited the phosphorylation of dynein-related protein 1-serine site 616 (DRP1S616), resulting in weakened mitochondrial fission function and increased mitochondrial DNA (mtDNA) release in hepatic stellate cell (HSC), which in turn activated the cGMP-AMP synthase (cGAS) pathway. Activation of the cGAS pathway induced a local inflammatory microenvironment that further stimulated liver fibrosis progression. Interestingly, in the NR1D1 overexpression model, we observed that DRP1S616 phosphorylation was restored, and cGAS pathway was also inhibited in HSCs, resulting in improved liver fibrosis. Taken together, our results suggest that targeting NR1D1 may be an effective approach to liver fibrosis prevention and management.
    Keywords:  Circadian clock; Liver fibrosis; M(6)A; Mitochondrial dynamics; NR1D1; Primary hepatic stellate cell
    DOI:  https://doi.org/10.1016/j.phrs.2023.106704
  25. Proc Natl Acad Sci U S A. 2023 Feb 28. 120(9): e2204933120
    Conserved reduction of m6A RNA modifications during aging and neurodegeneration is linked to changes in synaptic transcripts.
    Ricardo Castro-Hernández, Tea Berulava, Maria Metelova, Robert Epple, Tonatiuh Peña Centeno, Julia Richter, Lalit Kaurani, Ranjit Pradhan, M Sadman Sakib, Susanne Burkhardt, Momchil Ninov, Katherine E Bohnsack, Markus T Bohnsack, Ivana Delalle, Andre Fischer.
      N6-methyladenosine (m6A) regulates mRNA metabolism. While it has been implicated in the development of the mammalian brain and in cognition, the role of m6A in synaptic plasticity, especially during cognitive decline, is not fully understood. In this study, we employed methylated RNA immunoprecipitation sequencing to obtain the m6A epitranscriptome of the hippocampal subregions CA1, CA3, and the dentate gyrus and the anterior cingulate cortex (ACC) in young and aged mice. We observed a decrease in m6A levels in aged animals. Comparative analysis of cingulate cortex (CC) brain tissue from cognitively intact human subjects and Alzheimer's disease (AD) patients showed decreased m6A RNA methylation in AD patients. m6A changes common to brains of aged mice and AD patients were found in transcripts linked to synaptic function including calcium/calmodulin-dependent protein kinase 2 (CAMKII) and AMPA-selective glutamate receptor 1 (Glua1). We used proximity ligation assays to show that reduced m6A levels result in decreased synaptic protein synthesis as exemplified by CAMKII and GLUA1. Moreover, reduced m6A levels impaired synaptic function. Our results suggest that m6A RNA methylation controls synaptic protein synthesis and may play a role in cognitive decline associated with aging and AD.
    Keywords:  Alzheimer’s disease; RNA-methylation; epi-transcriptomics; epigenetics; neuro-epigenetics
    DOI:  https://doi.org/10.1073/pnas.2204933120
  26. J Cancer Res Clin Oncol. 2023 Feb 24.
    Molecular phenotypic linkage between N6-methyladenosine methylation and tumor immune microenvironment in hepatocellular carcinoma.
    Feng Zhang, Junming Bi, Jiasheng Liao, Wenhui Zhong, Min Yu, Xin Lu, Jinhui Che, Zhiyuan Chen, Haobin Xu, Shixiong Hu, Yubin Liu, Shuijiao Guo.
       PURPOSE: The crucial role of N6-methyladenosine (m6A) methylation in anti-tumor immunity and immunotherapy has been broadly depicted. However, the molecular phenotypic linkages between m6A modification pattern and immunological ecosystem are expected to be disentangled in hepatocellular carcinoma (HCC), for immunotherapeutic unresponsiveness circumvention and combination with promising drug agents.
    METHODS: Modification patterns of m6A methylation were qualitatively dissected according to the large-scale HCC samples profiling. We then determined the immune phenotypic linkages by systematically evaluating their tumor microenvironment composition, immune/stromal-relevant signature, immune checkpoints correlation, and prognostic value. Individual quantification of m6A methylation pattern was achieved by m6Ascore construction, intensified by longitudinal single-cell analysis of immunotherapy cohort and validated by the transcriptomic profiles of our in-hospital GDPH-HCC cohort. Candidate therapeutic agents were also screened out.
    RESULTS: Three distinct m6A methylation patterns were determined in high accordance with inflamed-, excluded-, and desert-immunophenotype. To be precise, Immune-inflamed high-m6Ascore group was characterized by activated immunity with favorable prognosis. Stromal activation and absence of immune cell infiltration were observed in low-m6Ascore phenotype, linked to impaired outcome. Patients with low-m6Ascore demonstrated diminished responses and clinical benefits for cohorts receiving immunotherapy. The above credible linkage between m6A methylation pattern and tumor immune microenvironment was robustly validated in our GDPH-HCC cohort. Single-cell dynamic change of m6A methylation level in exhausted CD8 T cell and fibroblast was depicted in immunotherapy cohort fore and art. Derived from m6A methylation pattern, seven potential frontline drug agents were recognized as promising choice for high-m6Ascore patients.
    CONCLUSION: Our work bridged the credible linkage between epigenetics and anti-tumor immunity in HCC, unraveling m6A modification pattern as immunological indicator and predictor for immunotherapy. Individualized m6Ascore facilitated strategic choices to maximize therapy-responsive possibility.
    Keywords:  Epigenetic modification; Hepatocellular carcinoma; Immune microenvironment; Immunotherapy; m6A methylation
    DOI:  https://doi.org/10.1007/s00432-023-04589-2
  27. Cell Death Dis. 2023 Feb 18. 14(2): 139
    m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization.
    Ning Wang, Ri-Xin Chen, Min-Hua Deng, Wen-Su Wei, Zhao-Hui Zhou, Kang Ning, Yong-Hong Li, Xiang-Dong Li, Yun-Lin Ye, Jun-Hua Wen, Biao Dong, Xue-Pei Zhang, Zhuo-Wei Liu, Fang-Jian Zhou.
      The significance of 5-methylcytosine (m5C) methylation in human malignancies has become an increasing focus of investigation. Here, we show that m5C regulators including writers, readers and erasers, are predominantly upregulated in urothelial carcinoma of the bladder (UCB) derived from Sun Yat-sen University Cancer Center and The Cancer Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a methyltransferase and Aly/REF export factor (ALYREF) as a nuclear m5C reader, are frequently coexpressed in UCB. By applying patient-derived organoids model and orthotopic xenograft mice model, we demonstrate that ALYREF enhances proliferation and invasion of UCB cells in an m5C-dependent manner. Integration of tanscriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) and RNA Immunoprecipitation (RIP)-seq analysis revealed that ALYREF specifically binds to hypermethylated m5C site in RAB, member RAS oncogene family like 6 (RABL6) and thymidine kinase 1 (TK1) mRNA via its K171 domain. ALYREF controls UCB malignancies through promoting hypermethylated RABL6 and TK1 mRNA for splicing and stabilization. Moreover, ALYREF recognizes hypermethylated m5C site of NSUN2, resulting in NSUN2 upregulation in UCB. Clinically, the patients with high coexpression of ALYREF/RABL6/TK1 axis had the poorest overall survival. Our study unveils an m5C dependent cross-regulation between nuclear reader ALYREF and m5C writer NSUN2 in activation of hypermethylated m5C oncogenic RNA through promoting splicing and maintaining stabilization, consequently leading to tumor progression, which provides profound insights into therapeutic strategy for UCB.
    DOI:  https://doi.org/10.1038/s41419-023-05661-y
  28. Biochem Pharmacol. 2023 Feb 21. pii: S0006-2952(23)00051-5. [Epub ahead of print] 115460
    The role of m6A-mediated PD-1/PD-L1 in antitumor immunity.
    Li Liu, Long Liang, Hui Li, Wenjun Shao, Chaoying Yang, Feng Lin, Jing Liu, Ji Zhang.
      N6-methyladenosine (m6A) is the most prevalent, abundant and conserved type of internal posttranscriptional RNA modification in eukaryotic cells. Emerging evidence suggests that m6A modifications perform important functions that affect antitumor immunity. Programmed death 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) are the two most well-studied immune checkpoint pathways. The interaction of PD-L1 with its receptor PD-1 inhibits cytotoxic T-cell-mediated tumor responses, and blockade of this interaction has proven to be an effective immunotherapy strategy in various cancers. Unfortunately, few cancer patients benefit from the two tools due to uncertain resistance. m6A plays an important role in affecting RNA biogenesis and process in various cancers. Understanding the molecular mechanism of drug resistance will promote the development of personalized clinical management. In this review, we systematically discussed the mechanisms by which m6A regulates PD-1 and PD-L1 expression and further their functions in the process of tumor immunotherapy and the potential application prospects of m6A-associated molecules. Moreover, mounting m6Ascore is established to evaluate the prognosis of cancer.
    Keywords:  N6-methyladenosine; PD-1; PD-L1; cancer; immunotherapy
    DOI:  https://doi.org/10.1016/j.bcp.2023.115460
  29. Arch Insect Biochem Physiol. 2023 Feb 19. e22005
    RNA methyltransferase BmMettl3 and BmMettl14 in silkworm (Bombyx mori) and the regulation of silkworm embryonic development.
    Bing Li, Pei Hu, Zhi-Hao Huang, Jia-Yue Yang, Jie Wang, Xiu-Zhi Xie, Yu-Han Wang, Chen-Chen Li, Jia-Ping Xu.
      N6-methyladenosine (m6A) is a ubiquitous reversible epigenetic RNA modification that plays an important role in regulating many biological processes, especially embryonic development. However, regulation of m6A methylation during silkworm embryonic development and diapause remains to be investigated. In this study, we analyzed the phylogeny of subunits of methyltransferases BmMettl3 and BmMettl14, and detected the expression patterns of BmMettl3 and BmMettl14 in different tissues and at different developmental stages in silkworm. To investigate the function of m6A on the development of silkworm embryo, we analyzed the m6A/A ratio in diapause and diapause termination eggs. The results showed that BmMettl3 and BmMettl14 were highly expressed in gonads and eggs. Moreover, the expression of BmMettl3 and BmMettl14 and the m6A/A ratio were significantly increased in diapause termination eggs compared with diapause eggs in the early stage of silkworm embryonic development. Furthermore, in BmN cell cycle experiments, the percentage of cells in the S phase increased when lacking BmMettl3 or BmMettl14. This work contributes to understanding the role of m6A methylation during insect embryogenesis and gametogenesis. It also provides a research orientation to further analyze the role of m6A methylation in diapause initiation and termination during insect embryonic development.
    Keywords:  Bombyx mori; cell cycle progression; diapause; embryonic development; m6A methyltransferase
    DOI:  https://doi.org/10.1002/arch.22005
  30. Cell Death Differ. 2023 Feb 24.
    N6-Methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2.
    Haibo Xia, Yan Wu, Jing Zhao, Cheng Cheng, Jiaheng Lin, Yi Yang, Lu Lu, Quanyong Xiang, Tao Bian, Qizhan Liu.
      Epithelial cell damage-initiated chronic obstructive pulmonary disease (COPD) is implicated in regulated cell death (RCD) including ferroptosis triggered by complex gene-environment interactions. Our data showed that iron overload and ferroptosis are associated with COPD progression in COPD patients and in experimental COPD. Furthermore, we found that, in lung tissues of COPD patients, circSAV1 was associated with COPD progression by circRNA-seq screening. Knockdown of circSAV1 reversed cigarette smoke extract (CSE)-induced ferroptosis. Mechanistically, m6A-modified circSAV1 formed an RNA-protein ternary complex of circSAV1/YTHDF1/IREB2 to facilitate the translation of IREB2 mRNA. Elevated protein levels of IREB2 disrupted iron homeostasis, resulting in accumulation of a labile iron pool (LIP) and lipid peroxidation, which contribute to ferroptosis. Here we demonstrate, by use of an experimental COPD model induced by cigarette smoke (CS), that silencing of circSAV1 and the treatment with deferoxamine (DFO) blocked CS-induced ferroptosis of lung epithelial cells, which attenuated COPD progression in mice. Our results reveal that N6-methyladenosine-modified circSAV1 triggers ferroptosis in COPD through recruiting YTHDF1 to facilitate the translation of IREB2, indicating that circSAV1 is a mediator of ferroptosis and that circSAV1-dependent ferroptosis is a therapeutic target for COPD. In lung epithelial cell, m6A-modified circSAV1, via recruiting YTHDF1, induces the formation of a circSAV1/YTHDF1/IREB2 mRNA protein ternary complex, which promotes translation of IREB2 mRNA. Further, elevated IREB2 contributes to the accumulation of a labile iron pool (LIP) and lipid peroxidation, then triggers ferroptosis of lung epithelial cells. The ferroptosis of airway epithelial cells and alveolar epithelial cells induces airway remodeling and emphysema, respectively, which causes COPD.
    DOI:  https://doi.org/10.1038/s41418-023-01138-9
  31. Biomolecules. 2023 Feb 01. pii: 273. [Epub ahead of print]13(2):
    The Epigenetic Regulation of RNA N6-Methyladenosine Methylation in Glycolipid Metabolism.
    Haiqing Yang, Yuting Li, Linying Huang, Miaochun Fang, Shun Xu.
      The highly conserved and dynamically reversible N6-methyladenine (m6A) modification has emerged as a critical gene expression regulator by affecting RNA splicing, translation efficiency, and stability at the post-transcriptional level, which has been established to be involved in various physiological and pathological processes, including glycolipid metabolism and the development of glycolipid metabolic disease (GLMD). Hence, accumulating studies have focused on the effects and regulatory mechanisms of m6A modification on glucose metabolism, lipid metabolism, and GLMD. This review summarizes the underlying mechanism of how m6A modification regulates glucose and lipid metabolism-related enzymes, transcription factors, and signaling pathways and the advances of m6A regulatory mechanisms in GLMD in order to deepen the understanding of the association of m6A modification with glycolipid metabolism and GLMD.
    Keywords:  N6-methyladenosine methylation; glucose metabolism; glycolipid metabolic disease; lipid metabolism
    DOI:  https://doi.org/10.3390/biom13020273
  32. Front Immunol. 2023 ;14 1075848
    A unique regulated cell death-related classification regarding prognosis and immune landscapes in non-small cell lung cancer.
    Wei Su, Ting Hong, Baijie Feng, Zhou Yang, Guang Lei.
      Regulated cell death (RCD) contributes to reshaping the tumor immune microenvironment and participating in the progression of non-small cell lung cancer (NSCLC); however, related mechanisms have not been fully disclosed. Here, we identified 5 subclusters of NSCLC based on consensus clustering of 3429 RCD-associated genes in the TCGA database and depicted the genomic features and immune landscape of these clusters. Importantly, the clusters provided insights into recognizing tumor microenvironment (TME) and tumor responses to immunotherapy and chemotherapy. Further, we established and validated an RCD-Risk model based on RCD-associated genes, which strongly predicted the prognosis, TME, and immunotherapy outcomes in NSCLC patients. Notably, tissue microarray staining confirmed that the expression of LDLRAD3, a core gene in RCD-Risk model, correlated with poor survival. In conclusion, we developed a novel RCD classification system and RCD-Risk model of NSCLC, serving as a robust and promising predictor for prognosis and immunotherapy benefit of individual NSCLC patients.
    Keywords:  immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; regulated cell death; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1075848
  33. Plant Physiol. 2023 Feb 22. pii: kiad112. [Epub ahead of print]
    m6A mRNA modification promotes chilling tolerance and modulates gene translation efficiency in Arabidopsis.
    Shuai Wang, Haiyan Wang, Zhihui Xu, Shasha Jiang, Yucheng Shi, Hairong Xie, Shu Wang, Jian Hua, Yufeng Wu.
      N 6-methyladenosine (m6A), the most prevalent mRNA modification in eukaryotes, is an emerging player of gene regulation at transcriptional and translational levels. Here we explored the role of m6A modification in response to low temperature in Arabidopsis (Arabidopsis thaliana). Knocking down mRNA adenosine methylase A (MTA), a key component of the modification complex, by RNA interference (RNAi) led to drastically reduced growth at low temperature, indicating a critical role of m6A modification in the chilling response. Cold treatment reduced the overall m6A modification level of mRNAs especially at the 3' untranslated region. Joint analysis of the m6A methylome, transcriptome and translatome of the wild type and the MTA RNAi line revealed that m6A-containing mRNAs generally had higher abundance and translation efficiency than non-m6A-containing mRNAs under normal and low temperatures. In addition, reduction of m6A modification by MTA RNAi only moderately altered the gene expression response to low temperature but led to dysregulation of translation efficiencies of one third of the genes of the genome in response to cold. We tested the function of the m6A-modified cold-responsive gene ACYL-COA:DIACYLGLYCEROL ACYLTRANSFERASE 1 (DGAT1) whose translation efficiency but not transcript level was reduced in the chilling-susceptible MTA RNAi plant. The dgat1 loss-of-function mutant exhibited reduced growth under cold stress. These results reveal a critical role of m6A modification in regulating growth under low temperature and suggest an involvement of translational control in chilling responses in Arabidopsis.
    Keywords:   DGAT1 ; MTA ; Arabidopsis; Chilling; Translation efficiency; m6A
    DOI:  https://doi.org/10.1093/plphys/kiad112
  34. Biomed Res Int. 2023 ;2023 1150768
    Identification of RALA as a Therapeutic Target and Prognostic Predictor of Osteosarcoma.
    Gentao Fan, Yan Zhu, Hao Zhu, Lingfeng Yu, Zhen Wang, Chenjun Zhai, Guangxin Zhou, Jianning Zhao, Yicun Wang.
       Background: Osteosarcoma (OS) is the most common primary aggressive sarcoma of bone, with massive aberrant expression of oncogenes related to the development of OS. RALA, a kind of small Ras-like guanosine triphosphatases, has been identified as a potential therapeutic target in several types of tumor, but its role in OS remains largely unknown.
    Methods: Abnormal expression of RALA was proven in the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and RNA-sequence of samples and cell lines. The role of RALA in OS was analyzed in terms of DNA methylation, immune cell infiltration, and patient survival. The cancer-promoting effect of RALA was demonstrated in cell lines and xenograft osteosarcoma models. A prognostic scoring model incorporating RALA as an indicator was established with the clinical samples that we collected.
    Results: The results showed that RALA was highly expressed in human OS tissues and cell lines. Survival analysis demonstrated that RALA was the sole independent risk factor for poor overall survival and disease-free survival in OS patients and impacted the proportion of infiltrating immune cells and DNA methylation in the OS tumor microenvironment. By gene-gene interaction analysis, we found that the expression of RALA was highly correlated to the expression of ABCE1. Similar to RALA, upregulated ABCE1 is correlated with poor survival outcome of OS patients. In addition, the functional experiment demonstrated that higher expression of RALA promoted the proliferation, migration, and invasion of OS cells. In vivo results were similar with the in vitro results. We examined m6a methylation-related genes and found that m6A methylation is responsible for the abnormal expression of RALA. Finally, the prognostic prediction model of RALA could be used to predict the long-term outcome of OS patients.
    Conclusions: We identified RALA as an oncogene in OS, and RALA upregulation in a concerted manner with ABCE1 was significantly associated with worse outcomes of OS patients. Targeting RALA may prove to be a novel target for OS immunotherapy in future clinical practice.
    DOI:  https://doi.org/10.1155/2023/1150768
  35. J Oncol. 2023 ;2023 7097909
    M6A Promotes Colorectal Cancer Progression via Regulating the miR-27a-3p/BTG2 Pathway.
    Wenjun Liu, Zilang Zhang, Xitu Luo, Kai Qian, Baojun Huang, Jianzhong Deng, Chengyu Yang.
      Long noncoding (lnc) RNAs regulate cancer progression. However, the importance of lncRNAs and how they are regulated in colorectal cancer (CRC) are unclear. We aim to evaluate the function of lncRNA ADAMTS9-AS2 in CRC and its fundamental mechanism. Levels of ADAMTS9-AS2, miR-27a-3p, and B-cell translocation gene 2 (BTG2) were measured by qPCR. Cell viability was analyzed by CCK-8 and colony formation. Migration and invasion were tested by transwell assay. The interactions among ADAMTS9-AS2, miR-27a-3p, BTG2, and YTHDF2 were analyzed by luciferase test, immunoblotting, RNA pull-down, or RNA immunoprecipitation (RIP). An animal model was adopted to assess ADAMTS9-AS2's function. Overexpressing ADAMTS9-AS2 inhibited cell migration, invasion, colony formation capacity, and proliferation in vitro. The direct targeting of miR-27a-3p by ADAMTS9-AS2 abrogated the latter's effect in CRC cells. BTG2 was identified a target of miR-27a-3p, and silencing BTG2 weakened miR-27a-3p's effect. Knocking down ADAMTS9-AS2 abolished sh-YTHDF2's inhibitory effect on cell proliferation and invasion. Finally, overexpressing ADAMTS9-AS2 restrained xenograft growth. M6A reader YTHDF2-mediated degradation of ADAMTS9-AS2 promotes colon carcinogenesis via miR-27a-3p/BTG2 axis.
    DOI:  https://doi.org/10.1155/2023/7097909
  36. Virchows Arch. 2023 Feb 23.
    Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.
    Ting Xue, Ru Yan, Zaishang Li, Shengjie Guo, Xiao Xiao, Jietian Jin, Lijuan Jiang, Huali Ma, Chong Wu, Tingyu Liu, Lichao Wei, Longbin Xiong, Fangjian Zhou, Kai Yao, Ranyi Liu, Hui Han.
      Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.
    Keywords:  Biomarker; Chemotherapy; FADD; Penile squamous cell carcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00428-023-03514-9
  37. Cell Mol Gastroenterol Hepatol. 2023 Feb 17. pii: S2352-345X(23)00024-3. [Epub ahead of print]
    Disruption to tRNA modification by queuine contributes to inflammatory bowel disease.
    Jilei Zhang, Yongguo Zhang, Callum J McGrenaghan, Vincent P Kelly, Yinglin Xia, Jun Sun.
       BACKGROUNDS AND AIMS: Transfer RNA (tRNA) is the most extensively modified RNA in cells. Queuosine (Q)-modification is a fundamental process for ensuring the fidelity and efficiency of translation from RNA to protein. In eukaryotes, tRNA-Q-modification relies on the intestinal microbial product queuine. However, the roles and potential mechanisms of Q-tRNA modifications in IBD are unknown.
    METHODS: We explored the Q-tRNA modifications and expression of Q tRNA ribosyltransferase catalytic subunit 1 (QTRT1) in patients with IBD by investigating human biopsies and reanalyzing datasets. We used colitis models, QTRT1-knockout mice, organoids, and cultured cells to investigate the molecular mechanisms of Q-tRNA modifications in intestinal inflammation.
    RESULTS: QTRT1 expression was significantly downregulated in ulcerative colitis and Crohn's disease patients. The four Q-tRNA-related tRNA synthetases (asparaginyl-, aspartyl-, histidyl-, and tyrosyl-tRNA synthetase) were decreased in IBD patients. This reduction was further confirmed in a DSS-induced colitis model and IL10-deficient mice. Reduced QTRT1 was significantly correlated with cell proliferation and intestinal junctions, including downregulation of β-catenin and Claudin-5 and the upregulation of Claudin-2. These alterations were confirmed in vitro by deleting the QTRT1 gene from cells and in vivo using QTRT1-knockout mice. Queuine treatment significantly enhanced cell proliferation and junction activity in cell lines and organoids. Queuine treatment also reduced inflammation in epithelial cells. Moreover, altered QTRT1-related metabolites were found in human IBD.
    CONCLUSION: TRNA modifications play an unexplored novel role in the pathogenesis of intestinal inflammation by altering epithelial proliferation and junction formation. Further investigation of the role of tRNA modifications will uncover novel molecular mechanisms for the prevention and treatment of IBD.
    Keywords:  IBD; QTRT1; proliferation; tRNA; tight junctions
    DOI:  https://doi.org/10.1016/j.jcmgh.2023.02.006
  38. bioRxiv. 2023 Feb 16. pii: 2023.02.16.528701. [Epub ahead of print]
    Redox Regulation of m 6 A Methyltransferase METTL3 in Human β-cells Controls the Innate Immune Response in Type 1 Diabetes.
    Dario F De Jesus, Zijie Zhang, Natalie K Brown, Xiaolu Li, Matthew J Gaffrey, Sevim Kahraman, Jiangbo Wei, Jiang Hu, Giorgio Basile, Ling Xiao, Tariq M Rana, Clayton Mathews, Alvin C Powers, Mark A Atkinson, Decio L Eizirik, Sirano Dhe-Paganon, Audrey V Parent, Wei-Jun Qian, Chuan He, Rohit N Kulkarni.
      Type 1 Diabetes (T1D) is characterized by autoimmune-mediated destruction of insulin-producing β-cells. Several observations have renewed interest in the innate immune system as an initiator of the disease process against β-cells. Here, we show that N 6 -Methyladenosine (m 6 A) is an adaptive β-cell safeguard mechanism that accelerates mRNA decay of the 2'-5'-oligoadenylate synthetase (OAS) genes to control the antiviral innate immune response at T1D onset. m 6 A writer methyltransferase 3 (METTL3) levels increase drastically in human and mouse β-cells at T1D onset but rapidly decline with disease progression. Treatment of human islets and EndoC-βH1 cells with pro-inflammatory cytokines interleukin-1 β and interferon α mimicked the METTL3 upregulation seen at T1D onset. Furthermore, m 6 A-sequencing revealed the m 6 A hypermethylation of several key innate immune mediators including OAS1, OAS2, and OAS3 in human islets and EndoC-βH1 cells challenged with cytokines. METTL3 silencing in human pseudoislets or EndoC-βH1 cells enhanced OAS levels by increasing its mRNA stability upon cytokine challenge. Consistently, in vivo gene therapy, to prolong Mettl3 overexpression specifically in β-cells, delayed diabetes progression in the non-obese diabetic (NOD) mouse model of T1D by limiting the upregulation of Oas pointing to potential therapeutic relevance. Mechanistically, the accumulation of reactive oxygen species blocked METTL3 upregulation in response to cytokines, while physiological levels of nitric oxide promoted its expression in human islets. Furthermore, for the first time to our knowledge, we show that the cysteines in position C276 and C326 in the zinc finger domain of the METTL3 protein are sensitive to S-nitrosylation (SNO) and are significant for the METTL3 mediated regulation of OAS mRNA stability in human β-cells in response to cytokines. Collectively, we report that m 6 A regulates human and mouse β-cells to control the innate immune response during the onset of T1D and propose targeting METTL3 to prevent β-cell death in T1D.
    DOI:  https://doi.org/10.1101/2023.02.16.528701
  39. Oxid Med Cell Longev. 2023 ;2023 3077091
    Deciphering the Role of Melatonin-Related Signatures in Tumor Immunity and the Prognosis of Clear Cell Renal Cell Carcinoma.
    Aimin Jiang, Chen Cai, Yiren Yang, Yankang Cui, Wenqiang Liu, Qingyang Pang, Zhenjie Wu, Bing Liu, Le Qu, Peng Luo, Anbang Wang, Linhui Wang.
       Methods: Adopting multiomics data from TCGA and other public datasets, we analysed the expression, mutation, and prognostic evaluation in multiple cancers. ccRCC patients were categorized into two subgroups by an unsupervised cluster algorithm: melatonin-pattern cancer subtype 1 (MPCS1) and subtype 2 (MPCS2). We then explored the immune microenvironment, immune therapy response, and tumor metabolic pathways between the two subtypes. The clinical characteristics, genomic mutation landscape, and molecular inhibitor response were further investigated. Finally, a melatonin regulator-related prognostic model was constructed to predict patient prognosis in ccRCC.
    Results: We found that melatonin regulators were dysregulated depending on distinct cancer types, which were associated with genomic variation. The two subtypes indicated different clinical characteristics and biological processes in ccRCC. MPCS2, an aggressive subtype, led an advanced clinical stage and poorer survival of ccRCC patients. The activated oncogenic signaling pathway and metabolic signatures were responsible for cancer progression in the MPCS2 subtype. The MPCS2 subgroup suggested a higher tumor mutational burden and immune dysfunction state, resulting in a lower response to immunotherapy. The copy number variations of MPCS2 were significantly more frequent than those of MPCS1. In addition, the two subgroups exhibited distinct drug responsiveness, with MPCS2 being less responsive to multiple drugs. Finally, we established a subtype biomarker-based prognostic risk model that exhibited satisfactory performance in ccRCC patients.
    Conclusion: Melatonin regulator-related features could remodel functional pathways and the tumor immune microenvironment through genomic mutations and pathway regulation. Melatonin regulator-associated molecular subtypes enhance the understanding of the molecular characteristics of renal cancer and can guide clinical treatment. Activating the melatonergic system axis may improve the effect of immunotherapy for ccRCC.
    DOI:  https://doi.org/10.1155/2023/3077091
  40. Biomolecules. 2023 Feb 08. pii: 326. [Epub ahead of print]13(2):
    Comprehensive Pan-Cancer Analysis of KIF18A as a Marker for Prognosis and Immunity.
    Ting Liu, Kun Yang, Jiamin Chen, Liming Qi, Xingang Zhou, Peng Wang.
      KIF18A belongs to the Kinesin family, which participates in the occurrence and progression of tumors. However, few pan-cancer analyses have been performed on KIF18A to date. We used multiple public databases such as TIMER, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Human Protein Atlas (HPA) to explore KIF18A mRNA expression in 33 tumors. We performed immunohistochemistry on liver cancer and pancreatic cancer tissues and corresponding normal tissues to examine the expression of KIF18A protein. Univariate Cox regression and Kaplan-Meier survival analysis were applied to detect the effect of KIF18A on overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of patients with these tumors. Subsequently, we explored KIF18A gene alterations in different tumor tissues using cBioPortal. The relationship between KIF18A and clinical characteristics, tumor microenvironment (TME), immune regulatory genes, immune checkpoints, tumor mutational burden (TMB), microsatellite instability (MSI), mismatch repairs (MMRs), DNA methylation, RNA methylation, and drug sensitivity was applied for further study using the R language. Gene Set Enrichment Analysis (GSEA) was utilized to explore the molecular mechanism of KIF18A. Bioinformatic analysis and immunohistochemical experiments confirmed that KIF18A was up-regulated in 27 tumors and was correlated with the T stage, N stage, pathological stage, histological grade, and Ki-67 index in many cancers. The overexpression of KIF18A had poor OS, DSS, and PFI in adrenocortical carcinoma (ACC), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), brain lower-grade glioma (LGG), liver cancer (LIHC), lung adenocarcinoma (LUAD), and pancreatic cancer (PAAD). Univariate and multivariate regression analysis confirmed KIF18A as an independent prognostic factor for LIHC and PAAD. The mutation frequency of KIF18A is the highest in endometrial cancer. KIF18A expression levels were positively associated with immunocyte infiltration, immune regulatory genes, immune checkpoints, TMB, MSI, MMRs, DNA methylation, RNA methylation, and drug sensitivity in certain cancers. In addition, we discovered that KIF18A participated in the cell cycle at the single-cell level and GSEA analysis for most cancers. These findings suggested that KIF18A could be regarded as a latent prognostic marker and a new target for cancer immunological therapy.
    Keywords:  KIF18A; immune cell infiltration; pan-cancer; prognosis
    DOI:  https://doi.org/10.3390/biom13020326
  41. Acta Biochim Biophys Sin (Shanghai). 2023 Feb 25.
    Expression pattern and prognostic value of key regulators for N7-methylguanosine RNA modification in prostate cancer.
    Qiliang Zhai, Yan Hou, Yuedian Ye, Sujuan Dai, Guangxiu Guo, Qiao Yang, Guofu Pang, Qiang Wei.
      Alterations in the regulators of RNA methylation modifications, such as N7-methylguanosine (m7G), have been implicated in a variety of diseases. Therefore, the analysis and identification of disease-related m7G modification regulators will accelerate advances in understanding disease pathogenesis. However, the implications of alterations in the regulators of m7G modifications remain poorly understood in prostate adenocarcinoma. In the present study, we analyze the expression patterns of 29 m7G RNA modification regulators in prostate adenocarcinoma using The Cancer Genome Atlas (TCGA) and perform consistent clustering analysis of differentially expressed genes (DEGs). We find that 18 m7G-related genes are differentially expressed in tumor and normal tissues. In different cluster subgroups, DEGs are mainly enriched in tumorigenesis and tumor development. Furthermore, immune analyses demonstrate that patients in cluster 1 have significantly higher scores for stromal and immune cells, such as B cells, T cells, and macrophages. Then, a TCGA-related risk model is developed and successfully validated using a Gene Expression Omnibus external dataset. Two genes ( EIF4A1 and NCBP2) are determined to be prognostically significant. Most importantly, we construct tissue microarrays from 26 tumor specimens and 20 normal specimens, and further confirm that EIF4A1 and NCBP2 are associated with tumor progression and Gleason score. Therefore, we conclude that the m7G RNA methylation regulators may be involved in the poor prognosis of patients with prostate adenocarcinoma. The results of this study may provide support for exploring the underlying molecular mechanisms of m7G regulators, especially EIF4A1 and NCBP2.
    Keywords:  Prostate cancer; RNA modification; m7G; tissue microarrays; tumor microenvironment
    DOI:  https://doi.org/10.3724/abbs.2023017
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