bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2020–11–08
seven papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Analysis of METTL3 and METTL14 in hepatocellular carcinoma.
  2. Gene Signatures and Prognostic Values of m6A Regulators in Hepatocellular Carcinoma.
  3. m6A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1.
  4. The momentous role of N6-methyladenosine in lung cancer.
  5. M6A RNA Methylation Regulator HNRNPC Contributes to Tumorigenesis and Predicts Prognosis in Glioblastoma Multiforme.
  6. Upregulated N6-methyladenosine RNA in Peripheral Blood: Potential Diagnostic Biomarker for Breast Cancer.
  7. The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.
  1. Aging (Albany NY). 2020 Nov 06. 12
    Analysis of METTL3 and METTL14 in hepatocellular carcinoma.
    Xiangxiang Liu, Jian Qin, Tianyi Gao, Chenmeng Li, Xiaoxiang Chen, Kaixuan Zeng, Mu Xu, Bangshun He, Bei Pan, Xueni Xu, Yuqin Pan, Huiling Sun, Tao Xu, Shukui Wang.
      N6-methyladenosine (m6A) RNA methylation is the most prevalent modification of messenger RNAs (mRNAs) and catalyzed by a multicomponent methyltransferase complex (MTC), among which methyltransferase-like 3 (METTL3) and METTL14 are two core molecules. However, METTL3 and METTL14 play opposite regulatory roles in hepatocellular carcinoma (HCC). Based on The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, we conducted a multi-omics analysis of METTL3 and METTL14 in HCC, including RNA-sequencing, m6ARIP-sequencing, and ribosome-sequencing profiles. We found that the expression and prognostic value of METTL3 and METTL14 are opposite in HCC. Besides, after METTL3 and METTL14 knockdown, most of the dysregulated mRNAs, signaling pathways and biological processes are distinct in HCC, which partly explains the contrary regulatory role of METTL3 and METTL14. Intriguingly, these mRNAs whose stability or translation efficiency are influenced by METTL3 or METTL14 in an m6A dependent manner, jointly regulate multiple signaling pathways and biological processes, which supports the cooperative role of METTL3 and METTL14 in catalyzing m6A modification. In conclusion, our study further clarified the contradictory role of METTL3 and METTL14 in HCC.
    Keywords:  METTL14; METTL3; N6-methyladenosine; bioinformatics analysis; hepatocellular carcinoma
    DOI:  https://doi.org/10.18632/aging.103959
  2. Front Genet. 2020 ;11 540186
    Gene Signatures and Prognostic Values of m6A Regulators in Hepatocellular Carcinoma.
    Pei Wang, Xiaotong Wang, Lei Zheng, Chunbo Zhuang.
      N6-methyladenosine (m6A) is the most abundant mRNA modification in mammals and has been implicated in various biological processes. However, its role in hepatocellular carcinoma (HCC) remains largely unknown. In this study, we investigated the alterations of 19 main m6A regulatory genes in HCC and their association with clinicopathological features, including survival. The mutation, copy number variation (CNV) and clinical data of HCC patients were retrieved from The Cancer Genome Atlas (TCGA) database. We found that the m6A regulators had high frequent alterations in HCC. The alterations of m6A regulators were significantly associated with clinicopathological features as well as TP53 alteration. Patients with any mutation of the m6A regulatory genes had worse overall survival (OS) and disease free survival (DFS). Deletion of METTL16 or ALKBH5 predicted poor OS and DFS of HCC patients. Moreover, deletion of METTL16 was an independent risk factor for DFS. Low METT16 expression was association with activation of multiple metabolic pathways in HCC. Finally, by RT-PCR, we confirmed that METTL16 was downregulated in HCC, and that lower METTL16 expression was associated with poor OS. In conclusion, we reported a significant association between alterations of m6A regulators and clinicopathological features, and highlighted the importance of METTL16 among the 19 m6A regulators in HCC pathogenesis. These findings will provide new insights into the role of m6A modification in HCC.
    Keywords:  METTL16; TCGA; hepatocellular carcinoma; m6A; prognosis
    DOI:  https://doi.org/10.3389/fgene.2020.540186
  3. Front Oncol. 2020 ;10 553045
    m6A Reader HNRNPA2B1 Promotes Esophageal Cancer Progression via Up-Regulation of ACLY and ACC1.
    Huimin Guo, Bei Wang, Kaiyue Xu, Ling Nie, Yao Fu, Zhangding Wang, Qiang Wang, Shouyu Wang, Xiaoping Zou.
      N6-methyladenosine (m6A) modification is the most abundant modification on eukaryotic RNA. In recent years, lots of studies have reported that m6A modification and m6A RNA methylation regulators were involved in cancer progression. However, the m6A level and its regulators in esophageal cancer (ESCA) remain poorly understood. In this study, we analyzed the expression of m6A regulators using The Cancer Genome Atlas data and found 14 of 19 m6A regulators are significantly increased in ESCA samples. Then we performed a univariate Cox regression analysis and LASSO (least absolute shrinkage and selection operator) Cox regression model to investigate the prognostic role of m6A regulators in ESCA, and the results indicated that a two-gene prognostic signature including ALKBH5 and HNRNPA2B1 could predict overall survival of ESCA patients. Moreover, HNRNPA2B1 is higher expressed in high-risk scores subtype of ESCA, indicating that HNRNPA2B1 may be involved in ESCA development. Subsequently, we confirmed that the level of m6A and HNRNPA2B1 was significantly increased in ESCA. We also found that HNRNPA2B1 expression positively correlated with tumor diameter and lymphatic metastasis of ESCA. Moreover, functional study showed that knockdown of HNRNPA2B1 inhibited the proliferation, migration, and invasion of ESCA. Mechanistically, we found that knockdown of HNRNPA2B1 inhibited the expression of de novo fatty acid synthetic enzymes, ACLY and ACC1, and subsequently suppressed cellular lipid accumulation. In conclusion, our study provides critical clues to understand the role of m6A and its regulators in ESCA. Moreover, HNRNPA2B1 functions as an oncogenic factor in promoting ESCA progression via up-regulation of fatty acid synthesis enzymes ACLY and ACC1, and it may be a promising prognostic biomarker and therapeutic target for human ESCA.
    Keywords:  ACC1; ACLY; HNRNPA2B1; esophageal cancer; fatty acid synthesis; m6A
    DOI:  https://doi.org/10.3389/fonc.2020.553045
  4. J Cell Physiol. 2020 Nov 01.
    The momentous role of N6-methyladenosine in lung cancer.
    Ruiyao Xu, Gaozong Pang, Qing Zhao, Lin Yang, Shu Chen, Long Jiang, Yuxian Shen, Wei Shao.
      Lung cancer is the leading cause of cancer death worldwide. Although diagnostic methods and targeted drugs have been rapidly developed in recent years, the underlying molecular mechanisms in the pathogenesis of lung cancer remain enigmatic. The N6-methyladenosine (m6 A) modification is the most common modification of messenger RNA in eukaryotes and plays critical roles in many diseases, especially cancers. Ectopic m6 A modification is associated with human carcinogenesis, including lung cancer. The m6 A modification is mediated by methyltransferases (writers) and demethylases (erasers) and indirectly affects biological processes through the recruitment of specific reader proteins (readers). Many studies have shown that m6 A writers, erasers, and readers serve as specific and sensitive biomarkers for lung cancer diagnosis, prognosis, and therapy. This review summarizes recent studies on the biological functions of the m6 A modification in lung cancer and discusses the potential application of m6 A regulators in lung cancer diagnosis and therapeutics.
    Keywords:  RNA methylation; epitranscriptome; lung cancer; m6A; posttranscriptional modification
    DOI:  https://doi.org/10.1002/jcp.30136
  5. Front Oncol. 2020 ;10 536875
    M6A RNA Methylation Regulator HNRNPC Contributes to Tumorigenesis and Predicts Prognosis in Glioblastoma Multiforme.
    Li-Chong Wang, Shu-Hui Chen, Xiao-Li Shen, Dang-Chi Li, Hai-Yun Liu, Yu-Long Ji, Min Li, Kai Yu, Huan Yang, Jun-Jun Chen, Chong-Zhen Qin, Ming-Ming Luo, Qian-Xia Lin, Qiao-Li Lv.
      Glioblastoma multiforme (GBM) is the most malignant glioma with a high death rate. N6-methyladenosine (m6A) RNA methylation plays an increasingly important role in tumors. The current study aimed to determine the function of the regulators of m6A RNA methylation in GBM. We evaluated the difference, interaction, and correlation of these regulators with TCGA database. HNRNPC, WTAP, YTHDF2 and, YTHDF1 were significantly upregulated in GBM. To explore the expression characteristics of regulators in GBM, we defined two subgroups through consensus cluster. HNRNPC, WTAP, and YTHDF2 were significantly upregulated in the cluster2 which had a good overall survival (OS). To investigate the prognostic value of regulators, we used lasso cox regression algorithm to screen an independent prognostic risk characteristic based on the expression of HNRNPC, ZC3H13, and YTHDF2. The prognostic feature between the low and high-risk groups was significantly different (P < 0.05), which could predict significance of prognosis (area under the curve (AUC) = 0.819). Moreover, we used western blot, RT-PCR, and immunohistochemical staining to verify the expression of HNRNPC was associated with malignancy and development of gliomas. Similarly, the high expression of HNRNPC had a good prognosis. In conclusion, HNRNPC is a vital participant in the malignant progression of GBM and might be valuable for prognosis.
    Keywords:  glioblastoma multiforme; hnRNPC; m6A; prognosis; tumorigenesis
    DOI:  https://doi.org/10.3389/fonc.2020.536875
  6. Cancer Res Treat. 2020 Oct 27.
    Upregulated N6-methyladenosine RNA in Peripheral Blood: Potential Diagnostic Biomarker for Breast Cancer.
    Han Xiao, Xiaobo Fan, Rui Zhang, Guoqiu Wu.
       Purpose: An effective biomarker for the diagnosis of breast cancer (BC) and benign breast diseases (BBD) is crucial for improving the prognosis. We investigated whether N6-methyladenosine (m6A) can be a diagnostic biomarker of BC.
    Materials and Methods: We detected the contents of peripheral blood m6A in 62 patients with BC, 41 patients with BBD, and 41 normal controls (NCs) using the colorimetric method. The relative expression of the m6A regulated genes METTL14 and FTO was analyzed using quantitative real-time polymerase chain reaction.
    Results: m6A in peripheral blood RNA was significantly higher in patients with BC than that in patients with BBD (p < 0.0001) or the NCs (p < 0.0001). m6A was closely associated with the disease stage (from stage 0 to stage I-Ⅳ; p = 0.003). The receiver operating characteristic curve of m6A contained an area under the curve (AUC) value of 0.887 in BC, which was greater than that of CEA or CA153. The combination of m6A, CEA, and CA153 improved the AUC to 0.914. The up- and downregulated mRNA expression of METTL14 and FTO, respectively, might contribute to the increase of m6A in patients with BC. m6A combined with METTL14 and FTO improved the AUC to 0.929 with a specificity of 97.4% in the peripheral blood of patients with BC.
    Conclusion: The peripheral blood RNA of m6A might be a valuable biomarker for the diagnosis of BC.
    Keywords:  Benign breast diseases; Biomarker; Breast neoplasms; N6-methyladenosine; Peripheral blood RNA
    DOI:  https://doi.org/10.4143/crt.2020.870
  7. J Exp Med. 2021 Mar 01. pii: e20200829. [Epub ahead of print]218(3):
    The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function.
    Christopher Mapperley, Louie N van de Lagemaat, Hannah Lawson, Andrea Tavosanis, Jasmin Paris, Joana Campos, David Wotherspoon, Jozef Durko, Annika Sarapuu, Junho Choe, Ivayla Ivanova, Daniela S Krause, Alex von Kriegsheim, Christian Much, Marcos Morgan, Richard I Gregory, Adam J Mead, Dónal O'Carroll, Kamil R Kranc.
      The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.
    DOI:  https://doi.org/10.1084/jem.20200829
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