bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–03–07
twelve papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. m6A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.
  2. FTO regulates myoblast proliferation by controlling CCND1 expression in an m6A-YTHDF2-dependent manner.
  3. RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming.
  4. Effects of m6A modifications on signaling pathways in human cancer (Review).
  5. Expression and Prognostic Characteristics of m6A RNA Methylation Regulators in Colon Cancer.
  6. Comprehensive analysis of the transcriptome-wide m6A methylome in invasive malignant pleomorphic adenoma.
  7. Changes and relationship of N6-methyladenosine modification and Long non-coding RNAs in oxidative damage induced by cadmium in pancreatic β-cells.
  8. Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma.
  9. Genetic variants in m6A modification core genes are associated with glioma risk in Chinese children.
  10. mTORC1-chaperonin CCT signaling regulates m6A RNA methylation to suppress autophagy.
  11. FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2.
  12. Immunoprecipitation and Sequencing of Acetylated RNA.
  1. Front Genet. 2021 ;12 622233
    m6A RNA Methylation Regulators Act as Potential Prognostic Biomarkers in Lung Adenocarcinoma.
    Hongbo Wang, Xiangxuan Zhao, Zaiming Lu.
      N6-methyladenosine [m(6)A/m6A] methylation is one of the most common RNA modifications in eukaryotic cell mRNA and plays an important regulatory role in mRNA metabolism, splicing, translocation, stability, and translation. Previous studies have demonstrated that the m6A modification is highly associated with tumor cell proliferation, migration, and invasion. In the present study, five m6A regulatory factors have been revealed, namely heterogeneous nuclear ribonucleoprotein A2/B1(HNRNPA2B1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), Vir like m6A methyltransferase associated protein (KIAA1429/VIRMA), RNA binding motif protein 15 (RBM15) and methyltransferase like 3 (METTL3), which are closely related to the overall survival (OS) of patients with lung adenocarcinoma (LUAD). These five m6A regulatory factors exhibited potential prognostic value for the 1, 3, and 5-years survival outcomes of LUAD patients. Our findings revealed that several signaling pathways, such as cell cycle, DNA replication, RNA degradation, RNA polymerase, nucleotide excision repair and basal transcription factors, are activated in the high-risk group of LUAD patients.
    Keywords:  N6-methylAdenosine (m6A); cancer biomarker; epitranscriptomics; lung cancer; prognosis
    DOI:  https://doi.org/10.3389/fgene.2021.622233
  2. Exp Cell Res. 2021 Feb 27. pii: S0014-4827(21)00055-0. [Epub ahead of print]401(2): 112524
    FTO regulates myoblast proliferation by controlling CCND1 expression in an m6A-YTHDF2-dependent manner.
    Kaiping Deng, Zhen Zhang, Caifang Ren, Yaxu Liang, Xiaoxiao Gao, Yixuan Fan, Feng Wang.
      N6-Methyladenosine (m6A) modification is the most abundant chemical modification in mRNA, and it participates in various biological processes, such as cell differentiation and proliferation. However, little is known about the function of m6A demethylase fat mass and obesity-associated (FTO) in myoblast proliferation. Here, we demonstrated that knockdown of FTO can significantly inhibit myoblast proliferation and promote apoptosis. RNA sequencing analysis revealed that a lot of downregulated genes in FTO knockdown cells are associated with cell cycle and apoptosis. Furthermore, silencing FTO drastically decreased cyclin D1 (CCND1) expression through YTHDF2-mediated mRNA degradation, thereby delaying the progression of G1 phase, and leading to impaired myoblast proliferation. These findings unraveled that FTO regulates myoblast proliferation by controlling CCND1 expression in an m6A-YTHDF2-dependent manner, which highlights the critical roles of m6A modification in myoblast proliferation.
    Keywords:  Cell cycle; Cell proliferation; FTO; Myoblast; m(6)A modification
    DOI:  https://doi.org/10.1016/j.yexcr.2021.112524
  3. Nat Commun. 2021 03 02. 12(1): 1394
    RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming.
    Huilong Yin, Xiang Zhang, Pengyuan Yang, Xiaofang Zhang, Yingran Peng, Da Li, Yanping Yu, Ye Wu, Yidi Wang, Jinbao Zhang, Xiaochen Ding, Xiangpeng Wang, Angang Yang, Rui Zhang.
      N6-methyladenosine (m6A) is a reversible mRNA modification that has been shown to play important roles in various biological processes. However, the roles of m6A modification in macrophages are still unknown. Here, we discover that ablation of Mettl3 in myeloid cells promotes tumour growth and metastasis in vivo. In contrast to wild-type mice, Mettl3-deficient mice show increased M1/M2-like tumour-associated macrophage and regulatory T cell infiltration into tumours. m6A sequencing reveals that loss of METTL3 impairs the YTHDF1-mediated translation of SPRED2, which enhances the activation of NF-kB and STAT3 through the ERK pathway, leading to increased tumour growth and metastasis. Furthermore, the therapeutic efficacy of PD-1 checkpoint blockade is attenuated in Mettl3-deficient mice, identifying METTL3 as a potential therapeutic target for tumour immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-021-21514-8
  4. Oncol Rep. 2021 Apr;45(4): 1-12
    Effects of m6A modifications on signaling pathways in human cancer (Review).
    Fangyuan Liu, Xiulan Su.
      N6‑methyladenosine (m6A) is one of the most prevalent post‑transcriptional RNA modifications. The enzymes involved in the regulation of m6A include methyltransferase (writers), demethylase (erasers) and m6A recognition proteins (readers). Accumulating studies have demonstrated that m6A modifications have a distinct effect on various biological processes, including tumorigenesis, cell differentiation, embryonic development and neurogenic diseases, while our knowledge of the specific mechanism underlying m6A methylation in various cancer types is still limited. Various signaling pathways have an effect on tumorigenesis, invasion and apoptosis of malignant tumors. The present review summarizes the recent progress in research regarding the role of m6A in human cancer and discusses the influence of m6A on classic signaling pathways in malignant tumors.
    DOI:  https://doi.org/10.3892/or.2021.7987
  5. Int J Mol Sci. 2021 Feb 21. pii: 2134. [Epub ahead of print]22(4):
    Expression and Prognostic Characteristics of m6A RNA Methylation Regulators in Colon Cancer.
    Liting Huang, Jie Zhu, Weikaixin Kong, Peifeng Li, Sujie Zhu.
      Colon cancer is a common and leading cause of death and malignancy worldwide. N6-methylation of adenosine (m6A) is the most common reversible mRNA modification in eukaryotes, and it plays a crucial role in various biological functions in vivo. Dysregulated expression and genetic changes of m6A regulators have been correlated with tumorigenesis, cancer cell proliferation, tumor microenvironment, and prognosis in cancers. This study used RNA-seq and colon cancer clinical data to explore the relationship between N6-methylation and colon cancer. Based on the seven m6A regulators related to prognosis, three molecular subgroups of colon cancer were identified. Surprisingly, we found that each subgroup had unique survival characteristics. We then identified three subtypes of tumors based on 299 m6A phenotype-related genes, and one subtype was characterized as an immunosuppressive tumor and patients in this subtype may be more suitable for immunotherapy than other subtypes. Finally, using m6A-related genes and clinical information from The Cancer Genome Atlas cohort, we constructed a prognosis model, and this model could be used to predict the prognosis of patients in clinics.
    Keywords:  colon cancer; immunity; m6A regulators; prognosis
    DOI:  https://doi.org/10.3390/ijms22042134
  6. Cancer Cell Int. 2021 Mar 02. 21(1): 142
    Comprehensive analysis of the transcriptome-wide m6A methylome in invasive malignant pleomorphic adenoma.
    Zhenyuan Han, Biao Yang, Qin Wang, Yuhua Hu, Yuqiong Wu, Zhen Tian.
       BACKGROUND: Invasive malignant pleomorphic adenoma (IMPA) is a highly invasive parotid gland tumor and lacks effective therapy. N6-Methyladenosine (m6A) is the most prevalent post-transcriptional modification of mRNAs in eukaryotes and plays an important role in the pathogenesis of multiple tumors. However, the significance of m6A-modified mRNAs in IMPA has not been elucidated to date. Hence, in this study, we attempted to profile the effect of IMPA in terms of m6A methylation in mRNA.
    METHODS: Methylated RNA immunoprecipitation with next-generation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were utilized to acquire the first transcriptome-wide profiling of the m6A methylome map in IMPA followed by bioinformatics analysis.
    RESULTS: In this study, we obtained m6A methylation maps of IMPA samples and normal adjacent tissues through MeRIP-seq. In total, 25,490 m6A peaks associated with 13,735 genes were detected in the IMPA group, whereas 33,930 m6A peaks associated with 18,063 genes were detected in the control group. Peaks were primarily enriched within coding regions and near stop codons with AAACC and GGAC motifs. Moreover, functional enrichment analysis demonstrated that m6A-containing genes were significantly enriched in cancer and metabolism relevant pathways. Furthermore, we identified a relationship between the m6A methylome and the RNA transcriptome, indicating a mechanism by which m6A modulates gene expression.
    CONCLUSIONS: Our study is the first to provide comprehensive and transcriptome-wide profiles to determine the potential roles played by m6A methylation in IMPA. These results may open new avenues for in-depth research elucidating the m6A topology of IMPA and the molecular mechanisms governing the formation and progression of IMPA.
    Keywords:  Malignant pleomorphic adenoma; MeRIP-seq; N6-Methyladenosine
    DOI:  https://doi.org/10.1186/s12935-021-01839-6
  7. Toxicol Lett. 2021 Feb 24. pii: S0378-4274(21)00060-6. [Epub ahead of print]
    Changes and relationship of N6-methyladenosine modification and Long non-coding RNAs in oxidative damage induced by cadmium in pancreatic β-cells.
    Tengjiao Qu, Yahao Mou, Jiao Dai, Xiaoli Zhang, Mengzhu Li, Shiyan Gu, Zuoshun He.
      N6-methyladenosine (m6A) modification and m6A-modified Long non-coding RNAs (LncRNAs) play crucial roles in various pathological processes, yet their changes and relationship in cadmium-induced oxidative damage are largely unknown. Here, five m6A-modified LncRNAs (LncRNA-TUG1, LncRNA-PVT1, LncRNA-MALAT1, LncRNA-XIST, LncRNA-NEAT1), which have been evidenced to involve in oxidative damage, were selected and their binding proteins were submitted to bioinformatics analysis. Our analysis results showed that these five m6A-modified LncRNAs bound to different regulatory proteins of m6A modification, implicating that m6A modification on LncRNAs may synergistically control by multiple regulatory proteins. Furthermore, the detection data revealed that levels of m6A modification, methyltransferase-like 3 (METTL3) and fat mass and obesity-associated protein (FTO) were all significantly decreased in CdSO4-induced oxidative damage, which was demonstrated by increasing ROS accumulation and MDA contents as well as decreasing SOD activities. More importantly, LncRNA-MALAT1 and LncRNA-PVT1 indicated downward trend and showed positive relationship with m6A modification. Collectively, our results showed that m6A modification and m6A-modified LncRNAs may involve in oxidative damage induced by cadmium.
    Keywords:  Bioinformatics analysis; Cadmium sulfate; Long non-coding RNAs; N(6)-methyladenosine; Oxidative damage
    DOI:  https://doi.org/10.1016/j.toxlet.2021.02.014
  8. Theranostics. 2021 ;11(8): 3676-3693
    Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma.
    Chuanjie Zhang, Li Chen, Yihan Liu, Jingyi Huang, Ao Liu, Yang Xu, Yan Shen, Hongchao He, Danfeng Xu.
      Background: Methyltransferase-like 14 (METTL14) participates in tumorigenesis in several malignancies, but how METTL14 mediates the metastasis of renal cell carcinoma (RCC) has never been reported. Methods: Western blotting, quantitative real-time PCR, and immunohistochemistry were used to determine the mRNA and protein levels of relevant genes. Methylated RNA immunoprecipitation sequencing and RNA sequencing were utilized to screen potential targets of METTL14. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing were performed to investigate epigenetic alterations. The biological roles and mechanisms of METTL14/BPTF in promoting lung metastasis were confirmed in vitro and in vivo using cell lines, patient samples, xenograft models, and organoids. Results: Utilizing the TCGA-KIRC and Ruijin-RCC datasets, we found low expression of METTL14 in mRCC samples, which predicted poor prognosis. METTL14 deficiency promoted RCC metastasis in vitro and in vivo. Mechanistically, METTL14-mediated m6A modification negatively regulated the mRNA stability of bromodomain PHD finger transcription factor (BPTF) and depended on BPTF to drive lung metastasis. Accumulated BPTF in METTL14-deficient cells remodeled the enhancer landscape to reinforce several oncogenic crosstalk. Particularly, BPTF constituted super-enhancers that activate downstream targets like enolase 2 and SRC proto-oncogene nonreceptor tyrosine kinase, leading to glycolytic reprogramming of METTL14-/- cells. Finally, we determined the efficacy of the BPTF inhibitor AU1 in suppressing mRCC of patient-derived cells, mRCC-derived organoids (MDOs), and orthotopic xenograft models. Conclusions: Our study is the first to investigate the essential role of m6A modification and the METTL14/BPTF axis in the epigenetic and metabolic remodeling of mRCC, highlighting AU1 as a vital therapeutic candidate.
    Keywords:  BPTF; METTL14; glycolysis; metastatic RCC; super-enhancers
    DOI:  https://doi.org/10.7150/thno.55424
  9. Mol Ther Oncolytics. 2021 Mar 26. 20 199-208
    Genetic variants in m6A modification core genes are associated with glioma risk in Chinese children.
    Jing He, Li Yuan, Huiran Lin, Ao Lin, Huitong Chen, Ailing Luo, Zhenjian Zhuo, Xiaoping Liu.
      Glioma is a highly heritable disease with a strong genetic component. The N6-methyladenosine (m6A) modification core genes play important roles in the context of cancer. However, the effects of polymorphisms in the m6A modification core genes on the risk of pediatric glioma remain undefined. Here, we intended to demonstrate the relationship between 24 functional single-nucleotide polymorphisms (SNPs) in eight m6A modification core genes and glioma risk. Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma while accounting for the subtypes of glioma. A total of 171 glioma cases and 228 controls from South China were genotyped using a TaqMan assay. The WTAP rs7766006, YTHDF2 rs3738067, and FTO rs9939609 variants conferred a statistically significant increased risk of glioma, respectively. YTHDC1 rs2293595, YTHDC1 rs3813832, and FTO rs8047395 were associated with a significant inverse association with risk of glioma, respectively. The significant associations were more predominant in stratification analyses of certain subgroups. Functional annotations revealed that WTAP rs7766006 and YTHDF2 rs3738067 could be potential functional variants by increasing expression of WTAP and YTHDF2 mRNA, respectively. Overall, these findings implicate variants in the m6A modification core genes as playing a role in pediatric glioma etiology.
    Keywords:  Chinese; glioma; m6A; polymorphism; susceptibility
    DOI:  https://doi.org/10.1016/j.omto.2020.12.013
  10. Proc Natl Acad Sci U S A. 2021 Mar 09. pii: e2021945118. [Epub ahead of print]118(10):
    mTORC1-chaperonin CCT signaling regulates m6A RNA methylation to suppress autophagy.
    Hong-Wen Tang, Jui-Hsia Weng, Wen Xing Lee, Yanhui Hu, Lei Gu, Sungyun Cho, Gina Lee, Richard Binari, Cathleen Li, Min En Cheng, Ah-Ram Kim, Jun Xu, Zhangfei Shen, Chiwei Xu, John M Asara, John Blenis, Norbert Perrimon.
      Mechanistic Target of Rapamycin Complex 1 (mTORC1) is a central regulator of cell growth and metabolism that senses and integrates nutritional and environmental cues with cellular responses. Recent studies have revealed critical roles of mTORC1 in RNA biogenesis and processing. Here, we find that the m6A methyltransferase complex (MTC) is a downstream effector of mTORC1 during autophagy in Drosophila and human cells. Furthermore, we show that the Chaperonin Containing Tailless complex polypeptide 1 (CCT) complex, which facilitates protein folding, acts as a link between mTORC1 and MTC. The mTORC1 activates the chaperonin CCT complex to stabilize MTC, thereby increasing m6A levels on the messenger RNAs encoding autophagy-related genes, leading to their degradation and suppression of autophagy. Altogether, our study reveals an evolutionarily conserved mechanism linking mTORC1 signaling with m6A RNA methylation and demonstrates their roles in suppressing autophagy.
    Keywords:  autophagy; chaperonin containing Tailless complex polypeptide 1 (CCT); m6A RNA methylation; m6A methyltransferase complex (MTC); mTORC1
    DOI:  https://doi.org/10.1073/pnas.2021945118
  11. Mol Cancer. 2021 03 03. 20(1): 45
    FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2.
    Fei Xu, Jiajia Li, Mengdong Ni, Jingyi Cheng, Haiyun Zhao, Shanshan Wang, Xiang Zhou, Xiaohua Wu.
       BACKGROUND: The tumor suppressor FBW7 is the substrate recognition component of the SCF E3-ubiquitin ligase complex that mediates proteolytic degradation of various oncogenic proteins. However, the role of FBW7 in ovarian cancer progression remains inadequately understood.
    METHODS: IP-MASS, co-IP, immunohistochemistry, and western blotting were used to identify the potential substrate of FBW7 in ovarian cancer. The biological effects of FBW7 were investigated using in vitro and in vivo models. LC/MS was used to detect the m6A levels in ovarian cancer tissues. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of YTHDF2.
    RESULTS: We unveil that FBW7 is markedly down-regulated in ovarian cancer tissues and its high expression is associated with favorable prognosis and elevated m6A modification levels. Consistently, ectopic FBW7 inhibits ovarian cancer cell survival and proliferation in vitro and in vivo, while ablation of FBW7 empowers propagation of ovarian cancer cells. In addition, the m6A reader protein, YTHDF2, is identified as a novel substrate for FBW7. FBW7 counteracts the tumor-promoting effect of YTHDF2 by inducing proteasomal degradation of the latter in ovarian cancer. Furthermore, YTHDF2 globally regulates the turnover of m6A-modified mRNAs, including the pro-apoptotic gene BMF.
    CONCLUSIONS: Our study has demonstrated that FBW7 suppresses tumor growth and progression via antagonizing YTHDF2-mediated BMF mRNA decay in ovarian cancer.
    Keywords:  BMF; FBW7; N6-methyladenosine; Ubiquitination; YTHDF2
    DOI:  https://doi.org/10.1186/s12943-021-01340-8
  12. Bio Protoc. 2019 Jun 20. 9(12): e3278
    Immunoprecipitation and Sequencing of Acetylated RNA.
    Daniel Arango, David Sturgill, Shalini Oberdoerffer.
      Generation of the epitranscriptome through chemical modifications of protein-coding messenger RNAs (mRNAs) has emerged as a new mechanism of post-transcriptional gene regulation. While most mRNA modifications are methylation events, a single acetylated ribonucleoside has been described in eukaryotes, occurring at the N4-position of cytidine (N4-acetylcytidine or ac4C). Using a combination of antibody-based enrichment of acetylated regions and deep sequencing, we recently reported ac4C as a novel mRNA modification that is catalyzed by the N-acetyltransferase enzyme NAT10. In this protocol, we describe in detail the procedures to identify acetylated mRNA regions transcriptome-wide using acetylated RNA immunoprecipitation and sequencing (acRIP-seq).
    Keywords:  Epitranscriptome; N4-acetylcytidine; ac4C; acRIP-seq; mRNA modifications
    DOI:  https://doi.org/10.21769/BioProtoc.3278
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