bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–11–28
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression.
  2. The Roles of RNA N6-Methyladenosine in Regulating Stem Cell Fate.
  3. METTL14 suppresses growth and metastasis of renal cell carcinoma by decreasing long non-coding RNA NEAT1.
  4. m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK.
  5. Mettl3 promotes oxLDL-mediated inflammation through activating STAT1 signaling.
  6. The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity.
  7. m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Papillary Thyroid Carcinoma.
  8. Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer.
  9. DNA Methylation Modification Regulator-Mediated Molecular Clusters and Tumor Metabolic Characterization in Prostate Cancer.
  1. Cancer Cell Int. 2021 Nov 22. 21(1): 616
    Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression.
    Rong-Zhang He, Jing Jiang, Xinglin Hu, Ming Lei, Jia Li, Weihao Luo, Lili Duan, Zheng Hu, Yin-Yuan Mo, Di-Xian Luo, Wan-Xin Peng.
       BACKGROUND: UCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC).
    METHODS: qRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA ( http://gepia.cancer-pku.cn ).
    RESULTS: Our results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues.
    CONCLUSION: These results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.
    Keywords:  CRC; IGF2BP2; UCA1; m6A modification
    DOI:  https://doi.org/10.1186/s12935-021-02288-x
  2. Front Cell Dev Biol. 2021 ;9 765635
    The Roles of RNA N6-Methyladenosine in Regulating Stem Cell Fate.
    Runbi Ji, Xu Zhang.
      RNA N6-methyladenosine (m6A) modification has important regulatory roles in determining cell fate. The reversible methylation process of adding and removing m6A marks is dynamically regulated by a fine-tuned coordination of many enzymes and binding proteins. Stem cells have self-renewal and pluripotent potential and show broad prospects in regenerative medicine and other fields. Stem cells have also been identified in cancer, which is linked to cancer metastasis, therapy resistance, and recurrence. Herein, we aimed to review the molecular mechanism that controls the reversible balance of m6A level in stem cells and the effect of m6A modification on the balance between pluripotency and differentiation. Additionally, we also elaborated the association between aberrant m6A modification and the maintenance of cancer stem cells in many cancers. Moreover, we discussed about the clinical implications of m6A modification in cancer stem cells for cancer diagnosis and therapy.
    Keywords:  N6-methyladenosine; cancer; cell differentiation; post-transcriptional modifications; stem cell
    DOI:  https://doi.org/10.3389/fcell.2021.765635
  3. Cancer Sci. 2021 Nov 23.
    METTL14 suppresses growth and metastasis of renal cell carcinoma by decreasing long non-coding RNA NEAT1.
    Tao Liu, Hui Wang, Zhibin Fu, Zheng Wang, Jie Wang, Xinxin Gan, Anbang Wang, Linhui Wang.
      Growing evidence supports that N6-methyladenosine (m6A) modification acts as a critical regulator involved in tumorigenesis at the mRNA level. However, the role of m6A modification at the ncRNA level remains largely unknown. We found that methyltransferase-like 14 (METTL14) was significantly downregulated in renal cell carcinoma (RCC) tissues (n=580). Gain-of-function and loss-of-function experiments revealed that METTL14 attenuated the proliferation and migration ability of RCC cells in vivo and in vitro. The methylated RNA immunoprecipitation experiments identified that METTL14 decreased the expression of lncRNA nuclear enriched abundant transcript 1_1 (NEAT1_1) in an m6A-dependent manner. Mechanistically, RNA pull-down assay and RNA immunoprecipitation identified NEAT1_1 directly bound to m6A reader YTHDF2. Notably, YTHDF2 accelerated the degradation of NEAT1_1 by selectively recognizing METTL14-mediated m6A marks on NEAT1_1. Multivariate analysis suggested that METTL14 downregulation was associated with the malignant characteristics and predicted poor prognosis in RCC patients. In conclusion, our results uncover a newly identified METTL14-YTHDF2-NEAT1_1 signaling axis, which facilitates RCC growth and metastasis and provides fresh insight into RCC therapy.
    Keywords:  Long non-coding RNA; METTL14; Renal cell carcinoma; YTHDF2; m6A
    DOI:  https://doi.org/10.1111/cas.15212
  4. Genes (Basel). 2021 Oct 30. pii: 1747. [Epub ahead of print]12(11):
    m6A mRNA Methylation Regulates LKB1 to Promote Autophagy of Hepatoblastoma Cells through Upregulated Phosphorylation of AMPK.
    Guohui Li, Liang Deng, Nan Huang, Zhongqi Cui, Qi Wu, Ji Ma, Qiuhui Pan, Fenyong Sun.
      The N6-methyladenosine (m6A) RNA modification can regulate autophagy to modulate the growth and development of tumors, but the mechanism of m6A modification for the regulation of autophagy in hepatocellular carcinoma cells (HCC) remains unclear. In the study, the knockdown of the Wilms' tumor 1-associating protein (WTAP) was made in HCC to study the correlation between m6A modification and autophagy. A fluorescent confocal microscopy analysis showed that the knockdown of WTAP could facilitate the autophagy of HCC. A Western blot analysis showed that the level of p-AMPK was decreased in WTAP-knockdown HCC cells. Additionally, LKB1, the upstream kinase of AMPK, was regulated by WTAP and it could mediate the phosphorylation of AMPK in an m6A-dependent manner. Further studies revealed that the knockdown of WTAP could reduce the level of LKB1 mRNA with m6A. This could result in the increased stability of LKB1 mRNA to promote its expression. The knockdown of WTAP could upregulate the level of autophagy and inhibit HCC proliferation. However, the overexpression of WTAP could resist autophagic cell death.
    Keywords:  AMPK; HCC; LKB1; WTAP; autophagy
    DOI:  https://doi.org/10.3390/genes12111747
  5. J Clin Lab Anal. 2021 Nov 26. e24019
    Mettl3 promotes oxLDL-mediated inflammation through activating STAT1 signaling.
    Zhenwei Li, Qingqing Xu, Ning Huangfu, Xiaomin Chen, Jianhua Zhu.
       BACKGROUND: Atherosclerosis (AS) is the main cause of cerebrovascular diseases, and macrophages act important roles during the AS pathological process through regulating inflammation. Modification of the novel N(6)-methyladenine (m6A) RNA is reported to be associated with AS, but its role in AS is largely unknown. The aim of this study was to investigate the role and mechanism of m6A modification in inflammation triggered by oxidized low-density lipoprotein (oxLDL) in macrophages during AS.
    METHODS: RAW264.7 macrophage cells were stimulated with 40 μg/ml ox-LDL, Dot blot, Immunoprecipitation, western blot, Rip and chip experiments were used in our study.
    RESULTS: We found oxLDL stimulation significantly promoted m6A modification level of mRNA in macrophages and knockdown of Methyltransferase-Like Protein 3 (Mettl3) inhibited oxLDL-induced m6A modification and inflammatory response. Mettl3 promoted oxLDL-induced inflammatory response in macrophages through regulating m6A modification of Signal transducer and activator of transcription 1 (STAT1) mRNA, thereby affecting STAT1 expression and activation. Moreover, oxLDL stimulation enhanced the interaction between Mettl3 and STAT1 protein, promoting STAT1 transcriptional regulation of inflammatory factor expression in macrophages eventually.
    CONCLUSIONS: These results indicate that Mettl3 promotes oxLDL-triggered inflammation through interacting with STAT1 protein and mRNA in RAW264.7 macrophages, suggesting that Mettl3 may be as a potential target for the clinical treatment of AS.
    Keywords:  N6-methyladenosine; atherosclerosis; inflammation; methyltransferase-like protein 3; signal transducer and activator of transcription 1
    DOI:  https://doi.org/10.1002/jcla.24019
  6. Front Cardiovasc Med. 2021 ;8 763469
    The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity.
    Min Zhu, Yangong Liu, Yuanxiu Song, Shiqin Zhang, Chengwen Hang, Fujian Wu, Xianjuan Lin, Zenghui Huang, Feng Lan, Ming Xu.
      Cyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METTL3, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.
    Keywords:  JPH2; METTL3; cardiomyocyte; cardiotoxicity; cyclophosphamide; m6A methylation
    DOI:  https://doi.org/10.3389/fcvm.2021.763469
  7. Front Oncol. 2021 ;11 729887
    m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Papillary Thyroid Carcinoma.
    Fei Li, Qingmei Deng, Xiaoxi Pang, Shan Huang, Jingmiao Zhang, Xiaxia Zhu, Hong Chen, Xiuxia Liu.
      Recently, immune response modulation at the epigenetic level is illustrated in studies, but the possible function of RNA 5-methylcytosine (m5C) modification in cell infiltration within the tumor microenvironment (TME) is still unclear. Three different m5C modification patterns were identified, and high differentiation degree was observed in the cell infiltration features within TME under the above three identified patterns. A low m5C-score, which was reflected in the activated immunity, predicted the relatively favorable prognostic outcome. A small amount of effective immune infiltration was seen in the high m5C-score subtype, indicating the dismal patient survival. Our study constructed a diagnostic model using the 10 signature genes highly related to the m5C-score, discovered that the model exhibited high diagnostic accuracy for PTC, and screened out five potential drugs for PTC based on this m5C-score model. m5C modification exerts an important part in forming the TME complexity and diversity. It is valuable to evaluate the m5C modification patterns in single tumors, so as to enhance our understanding towards the infiltration characterization in TME.
    Keywords:  5-methylcytosine (m5C) modification; immune infiltration; papillary thyroid carcinoma (PTC); subtype; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2021.729887
  8. J Clin Lab Anal. 2021 Nov 23. e24118
    Expression and prognostic significance of m6A-related genes in TP53-mutant non-small-cell lung cancer.
    Zhuochen Zhao, Junhu Wan, Manman Guo, Yangxia Wang, Zhengwu Yang, Fuyou Zhou, Zhuofang Li, Liang Ming.
       BACKGROUND: TP53 is an important tumor suppressor gene on human 17th chromosome with its mutations more than 60% in tumor cells. Lung cancer is the highest incidence malignancy in men around the world. N-6 methylase (m6A) is an enzyme that plays an important role in mRNA splicing, translation, and stabilization. However, its role in TP53-mutant non-small-cell lung cancer (NSCLC) remains unknown.
    METHOD: First, we investigated 17 common m6A regulators' prognostic values in NSCLC. Then, after the establishment of risk signature, we explored the diagnostic value of m6A in TP53-mutant NSCLC. Finally, gene set enrichment analysis (GSEA), gene ontology (GO) enrichment analysis, and differential expression analysis were used to reveal the possible mechanism of m6A regulators affecting TP53-mutant NSCLC patients.
    RESULTS: Study showed that nine m6A regulators (YTHDC2, METTL14, FTO, METTL16, YTHDF1, HNRNPA2B1, RBM15, KIAA1429, and WTAP) were expressed differently between TP53-mutant and wild-type NSCLC (p < 0.05); and ALKBH5 and HNRNPA2B1 were associated with the prognostic of TP53-mutant patients. After construction of the risk signature combined ALKBH5 and HNRNPA2B1, we divided patients with TP53 mutations into high- and low-risk groups, and there was a significant survival difference between two groups. Finally, 338 differentially expression genes (DEGs) were found between high- and low-risk groups. GO enrichment analysis, PPI network, and GSEA enrichment analysis showed that m6A may affect the immune environment in extracellular and change the stability of mRNA.
    CONCLUSION: In conclusion, m6A regulators can be used as prognostic predictors in TP53-mutant patients.
    Keywords:  N-6 methylation; NSCLC; TP53 mutant; bioinformatics; prognostic
    DOI:  https://doi.org/10.1002/jcla.24118
  9. J Oncol. 2021 ;2021 2408637
    DNA Methylation Modification Regulator-Mediated Molecular Clusters and Tumor Metabolic Characterization in Prostate Cancer.
    Yanlong Zhang, Xuezhi Liang, Liyun Zhang, Dongwen Wang.
       Background: An increasing number of studies have indicated a close link between DNA methylation and tumor metabolism. However, the overall influence of DNA methylation on tumor metabolic characteristics in prostate cancer (PCa) remains unclear.
    Methods: We first explored the subtypes of DNA methylation modification regulators and tumor metabolic features of 1,205 PCa samples using clustering analysis and gene set variation analysis based on the mRNA levels of DNA methylation modification regulators. A DNA methylation-related score (DMS) was calculated using principal component analysis and the DNA methylation modification-related gene signatures to quantify DNA methylation characteristics. We then performed a meta-analysis to identify the hazard ratio of DMS in the six cohorts. In addition, a nomogram was drawn using univariate and multivariate Cox analyses based on the DMS and clinical variables. Finally, a drug sensitivity analysis of the DMS was performed based on the genomics of drug sensitivity in cancer datasets.
    Results: Three PCa clusters showing different DNA methylation modification patterns and tumor metabolic features were identified. A DMS system was established to quantify the characteristics of DNA methylation modification. PCa samples showed a differential metabolic landscape between the high and low DMS groups. The prognostic value of the DMS and nomogram was independently validated in multiple cohorts. A high DMS was associated with increases in the tumor mutation burden, copy number variation, and microsatellite instability; high tumor heterogeneity; and poor prognosis. Finally, DMS was closely related to different types of antitumor treatment.
    Conclusion: Improving the understanding of tumor metabolism by characterizing DNA methylation modification patterns and using the DMS may help clinicians predict prognosis and aid in more personalized antitumor therapy strategies for PCa.
    DOI:  https://doi.org/10.1155/2021/2408637
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