bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–02–13
ten papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Methyltransferase-like (METTL)14-mediated N6-methyladenosine modification modulates retinal pigment epithelial (RPE) activity by regulating the methylation of microtubule-associated protein (MAP)2.
  2. MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma.
  3. Novel insights into the interaction between N6-methyladenosine modification and circular RNA.
  4. METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis.
  5. m6A-dependent upregulation of TRAF6 by METTL3 is associated with metastatic osteosarcoma.
  6. A Broad m6A Modification Landscape in Inflammatory Bowel Disease.
  7. m6A-mRNA Methylation Regulates Gene Expression and Programmable m6A Modification of Cellular RNAs With CRISPR-Cas13b in Renal Cell Carcinoma.
  8. ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress.
  9. Comprehensive analysis of N6-methyladenosine regulators with the tumor immune landscape and correlation between the insulin-like growth factor 2 mRNA-binding protein 3 and programmed death ligand 1 in bladder cancer.
  10. Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.
  1. Bioengineered. 2022 Mar;13(3): 4773-4785
    Methyltransferase-like (METTL)14-mediated N6-methyladenosine modification modulates retinal pigment epithelial (RPE) activity by regulating the methylation of microtubule-associated protein (MAP)2.
    Lu Yin, Cong Ma, Shengping Hou, Xiang Ma.
      The expression of METTL14 is significantly reduced in patients with retinitis pigmentosa (RP). To clarify the significance of the N6-methyladenosine (m6A) RNA modification in RP, we examined phagocytosis, apoptosis, and cell cycle distribution in a human RPE cell line, ARPE-19, following lentivirus-mediated knockdown of METTL14. Differentially expressed genes and changes in m6A level were evaluated by RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (MeRIP-seq), respectively. The results showed that phagocytosis and proliferation were decreased whereas apoptosis was increased in RPE cells by METTL14 silencing. We found that METTL14 directly regulated m6A level and the expression of MAP2, as determined by RNA-seq, MeRIP-seq, MeRIP quantitative PCR, and the RNA pull-down assay. Additionally, MAP2 could bind to neuronal differentiation (NEUROD)1, a pathogenic gene in RPE-associated diseases. A family member of the YTH domain, (YTHDF)2 was recognized as an m6A reader of MAP2 mRNA. MAP2 overexpression had the same effects as METTL14 knockdown in RPE cells. Thus, METTL14 regulates the expression of MAP2 via the modification of m6A, resulting in the dysregulation of NEUROD1 and pathologic changes in RPE cells. These findings suggest that therapeutic strategies targeting the m6A modification of MAP2 or the METTL14/YTHDF2/MAP2/NEUROD1 signaling axis may be effective in the treatment of RPE-associated ocular diseases.
    Keywords:  MAP2; METTL14; NEUROD1; RNA methylation; YTHDF2; m6A; retinal pigment epithelial cells; retinitis pigmentosa
    DOI:  https://doi.org/10.1080/21655979.2022.2032968
  2. Cell Death Discov. 2022 Feb 08. 8(1): 53
    MYC-activated RNA N6-methyladenosine reader IGF2BP3 promotes cell proliferation and metastasis in nasopharyngeal carcinoma.
    Mingyu Du, Yi Peng, Yang Li, Wenyue Sun, Huanfeng Zhu, Jing Wu, Dan Zong, Lirong Wu, Xia He.
      N6-Methyladenosine (m6A) modification is the most abundant RNA modification in eukaryotic cells. IGF2BP3, a well-known m6A reader, is deregulated in many cancers, but its role in nasopharyngeal carcinoma (NPC) remains unclear. In this work, IGF2BP3 was upregulated in NPC tissues and cells. The high level of IGF2BP3 was positively related to late clinical stages, node metastasis, and poor outcomes. Moreover, IGF2BP3 accelerated NPC cell tumor progression and metastasis in vitro and vivo. Upstream mechanism analyses indicated that the high expression of IGF2BP3 in head and neck tumors was mainly due to mRNA level amplification. Luciferase assay and chromatin immunoprecipitation assay (CHIP) depicted that MYC was effectively bound to the promoter of IGF2BP3, thereby improving its transcriptional activity. Results also showed that IGF2BP3 was not only positively correlated with KPNA2 expression but also modulated the expression of KPNA2. m6A RNA immunoprecipitation (MeRIP) and RNA stability experiments verified that silencing IGF2BP3 significantly inhibited the m6A modification level of KPNA2, thereby stabilizing the mRNA stability of KPNA2. Rescue experiments proved that the effect of inhibiting or overexpressing IGF2BP3 on NPC cells was partly reversed by KPNA2. Collectively, MYC-activated IGF2BP3 promoted NPC cell proliferation and metastasis by influencing the stability of m6A-modified KPNA2. Our findings offer new insights that IGF2BP3 may serve as a new molecular marker and potential therapeutic target for NPC treatment.
    DOI:  https://doi.org/10.1038/s41420-022-00844-6
  3. Mol Ther Nucleic Acids. 2022 Mar 08. 27 824-837
    Novel insights into the interaction between N6-methyladenosine modification and circular RNA.
    Tao Xu, Bangshun He, Huiling Sun, Mengqiu Xiong, Junjie Nie, Shukui Wang, Yuqin Pan.
      As the most prevalent type of RNA modification in eukaryotes, N6-methyladenosine (m6A) can modulate RNA fates such as processing, splicing, maturation, export, stability, translation, and degradation. Circular RNAs (circRNAs), a novel type of non-coding RNA (ncRNAs) characterized by a covalently closed loop structure, play an essential role in various physiological and pathological processes. Extensive studies have revealed that m6A modification is widespread in circRNAs and influences their biogenesis and functions. Intriguingly, circRNAs can affect m6A modification by regulating m6A regulatory proteins. In this review, we summarize the characteristics and biological functions of m6A and circRNAs and focus on recent advances in the interaction of m6A modification and circRNAs. In addition, the potential clinical applications of m6A modification and circRNAs in diagnosis and therapeutic targets are discussed.
    Keywords:  N6-methyladenosine; biological functions; circular RNAs; clinical applications; m6A-modified circRNAs
    DOI:  https://doi.org/10.1016/j.omtn.2022.01.007
  4. Nat Cell Biol. 2022 Feb 10.
    METTL16 exerts an m6A-independent function to facilitate translation and tumorigenesis.
    Rui Su, Lei Dong, Yangchan Li, Min Gao, P Cody He, Wei Liu, Jiangbo Wei, Zhicong Zhao, Lei Gao, Li Han, Xiaolan Deng, Chenying Li, Emily Prince, Brandon Tan, Ying Qing, Xi Qin, Chao Shen, Meilin Xue, Keren Zhou, Zhenhua Chen, Jianhuang Xue, Wei Li, Hanjun Qin, Xiwei Wu, Miao Sun, Yunsun Nam, Chun-Wei Chen, Wendong Huang, David Horne, Steven T Rosen, Chuan He, Jianjun Chen.
      METTL16 has recently been identified as an RNA methyltransferase responsible for the deposition of N6-methyladenosine (m6A) in a few transcripts. Whether METTL16 methylates a large set of transcripts, similar to METTL3 and METTL14, remains unclear. Here we show that METTL16 exerts both methyltransferase activity-dependent and -independent functions in gene regulation. In the cell nucleus, METTL16 functions as an m6A writer to deposit m6A into hundreds of its specific messenger RNA targets. In the cytosol, METTL16 promotes translation in an m6A-independent manner. More specifically, METTL16 directly interacts with the eukaryotic initiation factors 3a and -b as well as ribosomal RNA through its Mtase domain, thereby facilitating the assembly of the translation-initiation complex and promoting the translation of over 4,000 mRNA transcripts. Moreover, we demonstrate that METTL16 is critical for the tumorigenesis of hepatocellular carcinoma. Collectively, our studies reveal previously unappreciated dual functions of METTL16 as an m6A writer and a translation-initiation facilitator, which together contribute to its essential function in tumorigenesis.
    DOI:  https://doi.org/10.1038/s41556-021-00835-2
  5. J Bone Oncol. 2022 Feb;32 100411
    m6A-dependent upregulation of TRAF6 by METTL3 is associated with metastatic osteosarcoma.
    Jing Wang, Wentao Wang, Xing Huang, Jiashi Cao, Shuming Hou, Xiangzhi Ni, Cheng Peng, Tielong Liu.
       Objectives: RNA N6-methyladenosine (m6A) is associated with tumorigenesis. The importance of methyltransferase-like 3 (METTL3) has been reported in cancer progression and metastasis. However, its role and molecular mechanism in osteosarcoma (OS), the most common primary bone tumor, is poorly studied. In this study, we aimed to investigate the functional role and underlying mechanism of METTL3 in the metastasis of OS.
    Methods: The expression differences of METTL3 between metastatic and non-metastatic OS tissues and patients with different Enneking stages were detected using RT-qPCR. METTL3 was artificially downregulated in the cells, followed by wound healing assay, Matrigel assay, immunofluorescence, in vivo tumorigenic assay, HE staining, and western blot. Transcriptome sequencing and m6A-seq was conducted to identify the downstream genes of METTL3, and RIP and dual-luciferase assays were performed for validation. The expression of TRAF6 in OS tissues was detected using RT-qPCR. Finally, the rescue experiments were conducted.
    Results: METTL3 was overexpressed in metastatic OS tissues, and downregulation of METTL3 decreased cell migration, invasion, epithelial-mesenchymal transition, and tumorigenic and metastatic activities. The m6A site was highly enriched in cells poorly expressing METTL3, and the m6A peak was mainly enriched in the exon region. METTL3 was positively correlated with TRAF6 in metastatic OS, and depletion of METTL3 resulted in the loss of TRAF6 expression in OS cells. Upregulation of TRAF6 contributed to metastases in vitro and in vivo.
    Conclusion: METTL3 is highly expressed in OS and enhances TRAF6 expression through m6A modification, thereby promoting the metastases of OS cells.
    Keywords:  METTL3; Metastases; Osteosarcoma; TRAF6; m6A
    DOI:  https://doi.org/10.1016/j.jbo.2022.100411
  6. Front Cell Dev Biol. 2021 ;9 782636
    A Broad m6A Modification Landscape in Inflammatory Bowel Disease.
    Kai Nie, Jun Yi, Yuanyuan Yang, Minzi Deng, Yan Yang, Tianyu Wang, Xuejie Chen, Zhaoyu Zhang, Xiaoyan Wang.
      Background and Aims: N6-Methyladenosine (m6A) is the most common post-transcriptional modification on eukaryotic mRNA, affecting the mRNA's fate. The role of m6A regulation in inflammatory bowel disease is unclear. Here, we investigated the m6A landscape in inflammatory bowel diseases (IBD). Methods: Eleven human IBD microarray datasets were recruited from the Gene Expression Omnibus database and four were selected as discovery cohorts. An RNA-seq dataset from the Inflammatory Bowel Disease Multi'omics Database was used as a validation cohort. m6A regulators were measured in volunteers' colonic samples. Consensus clustering and immune scoring were used to estimate the characteristics of m6A regulation in IBD. m6A-related characteristics of different sub-phenotypes, sample sources, and biological therapeutic responses were determined using seven independent datasets. Results: m6A modification involves methyltransferases (writers), demethylases (erasers), and methylation-reading proteins (readers). A wide interaction exists between m6A regulators and IBD risk genes. The IBD risk loci can also be modified by m6A modifications in the public m6A sequencing data. Furthermore, m6A regulators displayed extensive differential expression in four independent discovery cohorts that share common differential genes (IGF2BP2, HNRNPA2B1, ZCCHC4, and EIF3I). In the validated cohort and enrolled volunteers' colonic biopsy samples, the differential m6A regulators were reconfirmed. Two clusters of consensus clustering exhibit different immune phenotypes. m6A-modified positions exist in the core IBD immune cytokines. Another set of IBD datasets revealed m6A-related differences across clinical phenotypes, biological samples, and therapeutic response subgroups in IBD patients. Conclusion: Regulation of m6A methylation is widely involved in IBD occurrence and development. m6A modifications in risk variants, core cytokines, immune cells, and other proteins may deeply influence the pathophysiology and clinical phenotypes. Further studies are needed to determine its role in IBD.
    Keywords:  N6-methyladenosine; RNA modifications; biologics response; epigenetics; inflammatory bowel diseases
    DOI:  https://doi.org/10.3389/fcell.2021.782636
  7. Front Genet. 2021 ;12 795611
    m6A-mRNA Methylation Regulates Gene Expression and Programmable m6A Modification of Cellular RNAs With CRISPR-Cas13b in Renal Cell Carcinoma.
    Ying Gan, Aolin Li, Jun Liu, Xiaofei Wang, Zhenan Zhang, Qinhan Li, Xiongjun Ye, Lin Yao, Qian Zhang.
      Background: N6-methyladenosine (m6A) is the most extensive messenger RNA modification. Despite recent advances in the biological roles of m6A, its role in the development and progression of renal cell carcinoma (RCC) remains unclear. Methods: In this study, we gained the transcriptome-wide m6A profile and gene expression pattern in RCC and paired adjacent peritumoral tissues by meRIP-seq and RNA-seq. m6A modifications of mRNAs were validated by meRIP-qPCR in tissues, and targeted methylation or demethylation was validated by using a CRISPR-Cas13b-based tool in RCC cell lines. Results: Our findings showed that there were 13,805 m6A peaks among 5,568 coding gene transcripts (mRNAs) in adjacent tissues and 24,730 m6A peaks among 6,866 mRNAs in tumor tissues. Furthermore, m6A modification sites were usually located in the coding sequences (CDS), and some near the start and stop codons. Gene Ontology analysis revealed that coding genes had differential N6-methyladenosine sites and were enriched in kidney development and cancer-related signaling pathways. We also found that different levels of m6A modifications could regulate gene expression. Conclusion: In summary, our results provided evidence for studying the potential function of RNA m6A modification and m6A-mediated gene expression regulation in human RCC.
    Keywords:  CRISPR-Cas13b; Programmable Modification; Renal Cell Carcinoma; gene expression; m6A
    DOI:  https://doi.org/10.3389/fgene.2021.795611
  8. Front Cardiovasc Med. 2021 ;8 817304
    ALKBH5 Regulates SPHK1-Dependent Endothelial Cell Angiogenesis Following Ischemic Stress.
    Rajesh Kumari, Roshan Dutta, Prabhat Ranjan, Zainab Gbongbo Suleiman, Sumanta Kumar Goswami, Jing Li, Harish Chandra Pal, Suresh Kumar Verma.
       Background: Endothelial cells dysfunction has been reported in many heart diseases including acute myocardial infarction, and atherosclerosis. The molecular mechanism for endothelial dysfunction in the heart is still not clearly understood. We aimed to study the role of m6A RNA demethylase alkB homolog 5 (ALKBH5) in ECs angiogenesis during ischemic injury.
    Methods and Results: ECs were treated with ischemic insults (lipopolysaccharide and 1% hypoxia) to determine the role of ALKBH5 in ECs angiogenesis. siRNA mediated ALKBH5 gene silencing was used for examining the loss of function. In this study, we report that ALKBH5 levels are upregulated following ischemia and are associated with maintaining ischemia-induced ECs angiogenesis. To decipher the mechanism of action, we found that ALKBH5 is required to maintain eNOS phosphorylation and SPHK1 protein levels. ALKBH5 silencing alone or with ischemic stress significantly increased SPHK1 m6A mRNA methylation. In contrast, METTL3 (RNA methyltransferase) overexpression resulted in the reduced expression of SPHK1.
    Conclusion: We reported that ALKBH5 helps in the maintenance of angiogenesis in endothelial cells following acute ischemic stress via reduced SPHK1 m6A methylation and downstream eNOS-AKT signaling.
    Keywords:  RNA demethylase; SPHK1; angiogenesis; endothelia cell; ischemia; m6A RNA methylation
    DOI:  https://doi.org/10.3389/fcvm.2021.817304
  9. Cancer Cell Int. 2022 Feb 11. 22(1): 72
    Comprehensive analysis of N6-methyladenosine regulators with the tumor immune landscape and correlation between the insulin-like growth factor 2 mRNA-binding protein 3 and programmed death ligand 1 in bladder cancer.
    Jianfeng Cui, Yaofeng Zhu, Xiaochen Liu, Wenfu Wang, Xuewen Jiang, Yangyang Xia, Guanwen Zhou, Shouzhen Chen, Benkang Shi.
       BACKGROUND: N6-methyladenosine (m6A) is one of the most abundant post-transcriptional modifications of RNA. However, there is limited information about the potential roles of m6A regulators in tumor immunity. Therefore, in this study, we aimed to testify the functions of m6A regulators in bladder cancer as well as their association with the tumor immune landscape.
    METHODS: We reported the variation and expression levels of m6A regulators in the TCGA database and GTEx database of bladder cancer. Clusters, risk score patterns, and nomograms were constructed to evaluate the function and prognostic value of m6A regulators. Furthermore, we constructed nomogram to evaluate the prognosis of the individual patients. The correlation between insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and programmed cell death ligand 1 (PD-L1) was evaluated both in vitro and in vivo.
    RESULTS: We found that the tumor grade and DNA damage pathways were strongly correlated with distinct clusters. Furthermore, two risk score groups with six m6A regulators were identified using the least absolute shrinkage and selection operator (LASSO) and multivariable Cox regression analysis, which could be regarded as independent prognostic markers in patients with bladder cancer. The risk score pattern was linked to the tumor immune landscape, indicating a correlation between immune checkpoints and m6A regulators. Moreover, an m6A regulator, IGF2BP3, was found to be highly expressed in the tumor samples, regulating both the total and membrane-bound PD-L1 expression levels.
    CONCLUSIONS: The results of this study revealed that the m6A clusters and patterns play crucial roles in the regulation of tumor immunity, which may be used to develop comprehensive treatment strategies for the management of bladder cancer.
    Keywords:  Bladder cancer; IGF2BP3; Immune landscape; PD-L1; m6A
    DOI:  https://doi.org/10.1186/s12935-022-02456-7
  10. Mol Cancer. 2022 Feb 10. 21(1): 43
    Methyltransferase like 7B is a potential therapeutic target for reversing EGFR-TKIs resistance in lung adenocarcinoma.
    Huibin Song, Dongcheng Liu, Lingwei Wang, Kaisheng Liu, Chen Chen, Le Wang, Yi Ren, Bing Ju, Fuhua Zhong, Xingyu Jiang, Guangsuo Wang, Zhe-Sheng Chen, Chang Zou.
       BACKGROUND: Identification of potential novel targets for reversing resistance to Epidermal Growth Factor Receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) holds great promise for the treatment of relapsed lung adenocarcinoma (LUAD). In the present study, we aim to investigate the role of methyltransferase-like 7B (METTL7B) in inducing EGFR-TKIs resistance in LUAD and whether it could be a therapeutic target for reversing the resistance.
    METHODS: METTL7B-overexpressed LUAD cell lines, gefitinib and osimertinib-resistant Cell-Derived tumor Xenograft (CDX) and Patient-Derived tumor Xenograft (PDX) mouse models were employed to evaluate the role of METTL7B in TKIs resistance. Ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) was used to identify the metabolites regulated by METTL7B. Methylated RNA immunoprecipitation (MeRIP)-qPCR analysis was performed to measure the N6-methyladenosine (m6A) status of mRNA of METTL7B targeted genes. Gold nanocluster-assisted delivery of siRNA targeting METTL7B (GNC-siMETTL7B) was applied to evaluate the effect of METTL7B in TKIs resistance.
    RESULTS: Increased expression of METTL7B was found in TKIs-resistant LUAD cells and overexpression of METTL7B in LUAD cells induced TKIs resistance both in vitro and in vivo. Activated ROS-metabolism was identified in METTL7B-overexpressed LUAD cells, accompanied with upregulated protein level of GPX4, HMOX1 and SOD1 and their enzymatic activities. Globally elevated m6A levels were found in METTL7B-overexpressed LUAD cells, which was reduced by knock-down of METTL7B. METTL7B induced m6A modification of GPX4, HMOX1 and SOD1 mRNA. Knock-down of METTL7B by siRNA re-sensitized LUAD cells to gefitinib and osimertinib both in vitro and in vivo.
    CONCLUSIONS: This study uncovered a new critical link in METTL7B, glutathione metabolism and drug resistance. Our findings demonstrated that METTL7B inhibitors could be used for reversing TKIs resistance in LUAD patients.
    Keywords:  Glutathione metabolism; Lung adenocarcinomas; METTL7B; TKIs resistance; m6A modification
    DOI:  https://doi.org/10.1186/s12943-022-01519-7
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