bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–10–31
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. m6A RNA Immunoprecipitation Followed by High-Throughput Sequencing to Map N6-Methyladenosine.
  2. Role of N6-Methyladenosine (m6A) Methylation Regulators in Hepatocellular Carcinoma.
  3. RBM15 promotes hepatocellular carcinoma progression by regulating N6-methyladenosine modification of YES1 mRNA in an IGF2BP1-dependent manner.
  4. Protective mechanism of demethylase FTO in energy metabolism disorder of hypoxia/reoxygenation-induced cardiomyocytes.
  5. RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance.
  6. Circ0008399 interaction with WTAP promotes assembly and activity of the m6A methyltransferase complex and promotes cisplatin resistance in bladder cancer.
  7. Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3β.
  8. m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression.
  9. Expression and prognostic potential of ribosome 18S RNA m6A methyltransferase METTL5 in gastric cancer.
  1. Methods Mol Biol. 2022 ;2404 355-362
    m6A RNA Immunoprecipitation Followed by High-Throughput Sequencing to Map N6-Methyladenosine.
    Devi Prasad Bhattarai, Francesca Aguilo.
      N6-methyladenosine (m6A) is the most abundant internal modification on messenger RNAs (mRNAs) and long noncoding RNAs (lncRNAs) in eukaryotes. It influences gene expression by regulating RNA processing, nuclear export, mRNA decay, and translation. Hence, m6A controls fundamental cellular processes, and dysregulated deposition of m6A has been acknowledged to play a role in a broad range of human diseases, including cancer. m6A RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq or m6A-seq) is a powerful technique to map m6A in a transcriptome-wide level. After immunoprecipitation of fragmented polyadenylated (poly(A)+) rich RNA by using specific anti-m6A antibodies, both the immunoprecipitated RNA fragments together with the input control are subjected to massively parallel sequencing. The generation of such comprehensive methylation profiles of signal enrichment relative to input control is necessary in order to better comprehend the pathogenesis behind aberrant m6A deposition.
    Keywords:  Epitranscriptomics; METTL3; MeRIP-seq or m6A-seq; N6-Methyladenosine
    DOI:  https://doi.org/10.1007/978-1-0716-1851-6_19
  2. Front Oncol. 2021 ;11 755206
    Role of N6-Methyladenosine (m6A) Methylation Regulators in Hepatocellular Carcinoma.
    Nanfang Qu, Xiaotong Bo, Bin Li, Lei Ma, Feng Wang, Qinghua Zheng, Xuhua Xiao, Fengmei Huang, Yuanyuan Shi, Xuemei Zhang.
      Liver cancer is the fifth most common malignant tumor in terms of incidence and the third leading cause of cancer-related mortality globally. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Although great progress has been made in surgical techniques, hepatic artery chemoembolization, molecular targeting and immunotherapy, the prognosis of liver cancer patients remains very poor. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic cells and regulates various stages of the RNA life cycle. Many studies have reported that the abnormal expression of m6A-related regulators in HCC represent diagnostic and prognostic markers and potential therapeutic targets. In this review, firstly, we introduce the latest research on m6A-related regulators in detail. Next, we summarize the mechanism of each regulator in the pathogenesis and progression of HCC. Finally, we summarize the potential diagnostic, prognostic and therapeutic value of the regulators currently reported in HCC.
    Keywords:  N6-methyladenosine m6A; erasers; hepatocellular carcinoma; readers; writers
    DOI:  https://doi.org/10.3389/fonc.2021.755206
  3. Cell Death Discov. 2021 Oct 27. 7(1): 315
    RBM15 promotes hepatocellular carcinoma progression by regulating N6-methyladenosine modification of YES1 mRNA in an IGF2BP1-dependent manner.
    Xianlei Cai, Yunhao Chen, Da Man, Beng Yang, Xiaode Feng, Deguo Zhang, Junru Chen, Jian Wu.
      The function of the N6-methyladenosine (m6A) methyltransferase RNA-binding motif protein 15 (RBM15) in hepatocellular carcinoma (HCC) has not been thoroughly investigated. Here we determined the clinical value, biological functions, and potential mechanisms of RBM15 in HCC. Expression of RBM15 was identified using tissue microarrays and online databases. A risk-prediction model based on RBM15 was developed and validated. We determined the biological role of RBM15 on HCC cells in vitro and in vivo. RNA sequencing was used to screen candidate targets of RBM15. Subsequently, the m6A dot blot assay, methylated RNA immunoprecipitation qPCR, dual-luciferase reporter assays, RNA decay assay, and RNA immunoprecipitation qPCR were employed to explore the mechanisms of RBM15. Our study showed that RBM15 was highly expressed in HCC, and overexpression of RBM15 indicated a worse outcome. A new nomogram combining RBM15 with age and TNM stage was developed and validated to predict the outcome of HCC patients; our nomogram increased the prediction accuracy of the TNM system. Functionally, RBM15 facilitates the proliferation and invasiveness of HCC. RBM15-mediated m6A modification contributed to a post-transcriptional activation of YES proto-oncogene 1 (YES1) in an insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1)-dependent manner. In addition, YES1 was confirmed as an oncogene in HCC cells by activating the mitogen-activated protein kinase (MAPK) pathway. In conclusion, RBM15-mediated m6A modification might facilitate the progression of HCC via the IGF2BP1-YES1-MAPK axis. RBM15 may be a promising biomarker in the outcome prediction of HCC.
    DOI:  https://doi.org/10.1038/s41420-021-00703-w
  4. Exp Physiol. 2021 Oct 29.
    Protective mechanism of demethylase FTO in energy metabolism disorder of hypoxia/reoxygenation-induced cardiomyocytes.
    Wenzheng Deng, Qiao Jin, Liang Li.
       NEW FINDINGS: What is the central question of this study? FTO modification of M6A is associated with myocardial cell energy metabolism disorder, which has not been previously reported. What is the main finding and its importance? FTO reduced m6A level on SERCA2a mRNA through demethylation, thus promoting SERCA2a expression, maintaining calcium homeostasis, and improving energy metabolism of H/R cardiomyocytes.
    ABSTRACT: Energy metabolism disorder is the initial physiological link of myocardial ischemia-reperfusion injury. Fat mass and obesity-associated protein (FTO) is an N6 -methyladenosine (m6 A) demethylase implicated in several cardiac defects. This study sought to investigate the effect of FTO on energy metabolism in hypoxia/reoxygenation (H/R)-induced cardiomyocytes. FTO and sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a) expressions in H/R-induced cardiomyocytes were detected. The cardiomyocyte viability, cytotoxicity, and apoptosis were all measured respectively. The total RNA and polyA+ RNA contents were isolated from cells. The m6 A level of RNA and the enrichment of m6 A in SERCA2a were calculated. Several indices such as the glycolytic potential, reactive oxygen species (ROS), mitochondrial activity, and adenosine triphosphate (ATP) content were evaluated. The concentration of calcium in cardiomyocytes was detected. FTO and SERCA2a were poorly expressed in H/R-induced cardiomyocytes. Our results elicited an elevated m6 A level in total RNA and enrichment of m6 A in SERCA2a mRNA. H/R treatment reduced the cell viability, mitochondrial membrane potential, and ATP content in cardiomyocytes, but increased the cytotoxicity, apoptosis, ROS content, and calcium concentration. Upregulation of FTO reversed the preceding findings with down-regulation of the m6 A level of SERCA2a. Downregulation of SERCA2a annulled the promoting effect of FTO on calcium homeostasis and energy metabolism in H/R-induced cardiomyocytes. Collectively, the current study demonstrated that FTO reduced the m6 A level on SERCA2a mRNA through demethylation, thus promoting SERCA2a expression, maintaining calcium homeostasis, and improving the energy metabolism of H/R cardiomyocytes. This article is protected by copyright. All rights reserved.
    Keywords:  FTO; SERCA2a; calcium overload; cardiomyocytes; demethylase; energy metabolism disorder; hypoxia/reoxygenation; m6A
    DOI:  https://doi.org/10.1113/EP089901
  5. Med Sci Monit. 2021 Oct 25. 27 e930994
    RNA N6-Methyladenosine Patterns in Hepatocellular Carcinoma Reveal a Distinct Immune Infiltration Landscape and Clinical Significance.
    Hua Zhao, Qiujun Zhou, Chengwei Shi, Yaojian Shao, Junjie Ni, Jianying Lou, Shenyu Wei.
      BACKGROUND RNA N6-methyladenosine (m6A) methylation, the most abundant and prominent form of epigenetic modification, is involved in hepatocellular carcinoma (HCC) initiation and progression. However, the role of m6A methylation in HCC tumor microenvironment (TME) formation is unexplored. This study aimed to reveal the TME features of HCC patients with distinct m⁶A expression patterns and establish a prognostic model based on m⁶A signatures for HCC cohorts. MATERIAL AND METHODS We classified the m⁶A methylation patterns in 365 HCC samples based on 21 m6A modulators using a consensus clustering algorithm. Single-sample gene set enrichment analysis algorithm was used to quantify the abundance of immune cell infiltration. Gene set variation analysis revealed the biological characteristics between the m⁶A modification patterns. The m6A-based prognostic model was constructed using a training set with least absolute shrinkage and selection operator regression and validated in internal and external datasets. RESULTS Two distinct m⁶A modification patterns exhibiting different TME immune-infiltrating characteristics, heterogeneity, and prognostic variations were identified in the HCC cohort. After depicting the immune landscape of TME in HCC, we found patients with high LRPPRC m⁶A modulator expression had depletion of T cells, cytotoxic cells, dendritic cells, and cytolytic activity response. A high m⁶A score, characterized by suppression of immunity, indicated an immune-excluded TME phenotype, with poor survival. A nomogram was developed to facilitate HCC clinical decision making. CONCLUSIONS Our results highlight the nonnegligible role of m6A methylation in TME formation and reveal a potential clinical application of the m⁶A-associated prognostic model for patients with HCC.
    DOI:  https://doi.org/10.12659/MSM.930994
  6. Cancer Res. 2021 Oct 26. pii: canres.1518.2021. [Epub ahead of print]
    Circ0008399 interaction with WTAP promotes assembly and activity of the m6A methyltransferase complex and promotes cisplatin resistance in bladder cancer.
    Wenjie Wei, Jiayin Sun, Hui Zhang, Xingyuan Xiao, Chao Huang, Liang Wang, He Zhong, Yangkai Jiang, Xiaoping Zhang, Guosong Jiang.
      Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer (BC), yet most patients rapidly develop resistance. N6-methyladenosine (m6A) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in BC remain unclear. Furthermore, studies have not yet fully elucidated whether circRNA can directly regulate m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa_circ_0008399 (circ0008399), by eukaryotic translation initiation factor 4A3 (EIF4A3) in BC tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of BC cells. Mechanistically, circ0008399 bound Wilms' tumor 1-associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In BC patients, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399/WTAP/TNFAIP3 pathway decreased BC chemosensitivity to CDDP, and targeting the circ0008399/WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for BC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1518
  7. Clin Transl Med. 2021 Oct;11(10): e602
    Downregulation of microRNA-6125 promotes colorectal cancer growth through YTHDF2-dependent recognition of N6-methyladenosine-modified GSK3β.
    Hongyan Li, Ning Zhang, Xueli Jiao, Cong Wang, Wenhao Sun, Yanyu He, Ganglin Ren, Shirui Huang, Mengjie Li, Yixin Chang, Zihui Jin, Qipeng Xie, Xiaodong Zhang, Haishan Huang, Honglei Jin.
       BACKGROUND: MicroRNAs (miRNAs), the key regulator of gene expression, and N6-methyladenosine (m6A) RNA modification play a significant role in tumour progression. However, regulation of m6A-modified mRNAs by miRNAs in colorectal cancer (CRC), and its effect on progression of CRC, remains to be investigated.
    METHODS: Expression of miR-6125 and YTH Domain-Containing Family Protein 2 (YTHDF2) was detected by western blotting and immunohistochemistry. The effects of miR-6125 and YTHDF2 on proliferative capacity of CRC cells were analysed using soft agar, ATP, CCK8 and EdU assays, and in animal experiments.
    RESULTS: MiR-6125 expression was downregulated markedly in CRC, and expression correlated negatively with tumour size and prognosis. MiR-6125 targeted the 3'-UTR of YTHDF2 and downregulated the YTHDF2 protein, thereby increasing the stability of m6A-modified glycogen synthase kinase 3 beta (GSK3β) mRNA. Increased GSK3β protein levels inhibited the expression of Wnt/β-catenin/Cyclin D1 pathway-related proteins, leading to G0-G1 phase arrest and ultimately inhibiting the proliferation of CRC cells.
    CONCLUSIONS: MiR-6125 regulates YTHDF2 and thus plays a critical role in regulating the Wnt/β-catenin pathway, thereby affecting the growth of CRC. Collectively, these results suggest that miR-6125 and YTHDF2 are potential targets for treatment of CRC.
    Keywords:  GSK3β; Wnt/β-catenin; YTHDF2; cell cycle; colorectal cancer; m6A; miR-6125
    DOI:  https://doi.org/10.1002/ctm2.602
  8. Mol Ther Nucleic Acids. 2021 Dec 03. 26 637-648
    m6A modification of circHPS5 and hepatocellular carcinoma progression through HMGA2 expression.
    Dawei Rong, Fan Wu, Chen Lu, Guangshun Sun, Xiaoli Shi, Xiaoyuan Chen, Yongjiu Dai, Weizhe Zhong, Xiaopei Hao, Jinren Zhou, Yongxiang Xia, Weiwei Tang, Xuehao Wang.
      N6-methyladenosine (m6A) is capable of mediating circRNA generation in carcinoma biology. Nevertheless, the posttranscriptional systems of m6A and circRNA in hepatocellular carcinoma (HCC) development are still unclear. The present study identified a circRNA with m6A modification, circHPS5, which was increased in neoplasm HCC tissues and indicated poor patient survival. Silencing of circHPS5 inhibited epithelial-mesenchymal transition (EMT) and cancer stem-like cell (CSC) phenotypes. Notably, METTL3 could direct the formation of circHPS5, and specific m6A controlled the accumulation of circHPS5. YTHDC1 facilitated the cytoplasmic output of circHPS5 under m6A modification. In addition, we demonstrated that circHPS5 can act as a miR-370 sponge to regulate the expression of HMGA2 and further accelerate HCC cell tumorigenesis. Accordingly, the m6A modification of circHPS5 was found to modulate cytoplasmic output and increase HMGA2 expression to facilitate HCC development. The new regulatory model of "circHPS5-HMGA2" provides a new perspective for circHPS5 as an important prognostic marker and therapeutic target in HCC and provides mechanistic insight for exploring the carcinogenic mechanism of circHPS5 in HCC.
    Keywords:  HMGA2; circHPS5; circRNA; epithelial-mesenchymal transition; hepatocellular carcinoma; m6A modification
    DOI:  https://doi.org/10.1016/j.omtn.2021.09.001
  9. Cancer Cell Int. 2021 Oct 26. 21(1): 569
    Expression and prognostic potential of ribosome 18S RNA m6A methyltransferase METTL5 in gastric cancer.
    Zhenshuang Wang, Jingwei Liu, Yi Yang, Chenzhong Xing, Jingjing Jing, Yuan Yuan.
       BACKGROUND: Ribosomal RNA N6-methyltransferase METTL5 was reported to catalyze m6A in 18S rRNA. We aimed to investigate the expression and prognostic features of METTL5 in gastric cancer (GC).
    METHODS: In this study, 168 GC patients and their corresponding adjacent tissues were collected. Immunohistochemical staining was used to detect the expression of METTL5 protein. Univariate and multivariate Cox analysis were used to dertermine the prognostic role of METTL5 protein in GC, and a nomogram was constructed to evaluate GC patients' prognosis based on METTL5 expression. Data from TCGA and GEO database were also used to validate the prognostic value of METTL5 in GC patients on mRNA level. We further performed GSEA enrichment analysis to explore the possible function and related pathways related to METTL5.
    RESULTS: METTL5 protein in gastric cancer tissues (GCTs) was significantly decreased compared with adjacent normal tissues (ANTs) and adjacent intestinal metaplasia tissues (AIMTs) (P < 0.001, respectively). Meanwhile, METTL5 expression was negatively correlated with clinicopathologic stage. According to multivariate Cox proportional hazards model analysis, METTL5 protein expression was a good independent predictor of GC prognosis (p < 0.05). Patients with high METTL5 expression had better prognosis. The nomogram constructed based on METTL5 expression could predict the prognosis of GC patients well. GSEA analysis showed that genes of METTL5 low expression group were enriched in some oncogenic signaling pathways such as ERBB, MAPK, JAK-STAT, Wnt, and mTOR, as well as some immune pathways, including Fc-gamma R mediated phagocytosis, Fc-epsilon Ri, chemokine, T cell receptor and B cell receptor signaling pathway. While the high expression group of METTL5 was mainly related to oxidative phosphorylation, nucleotide excision repair and mismatch repair.
    CONCLUSIONS: METTL5 protein was decreased in GCTs compared with AIMTs and ANTs, and it may be a potential prognostic biomarker in GC.
    Keywords:  Gastric cancer; METTL5; Nomogram; Prognostic biomarkers
    DOI:  https://doi.org/10.1186/s12935-021-02274-3
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