bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–05–23
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. m6A regulators are associated with osteosarcoma metastasis and have prognostic significance: A study based on public databases.
  2. Functions of RNA N6-methyladenosine modification in acute myeloid leukemia.
  3. METTL3/METTL14 transactivation and m6A-dependent TGF-β1 translation in activated Kupffer cells.
  4. Understanding the roles of N6-methyladenosine writers, readers and erasers in breast cancer.
  5. Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer.
  6. The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth.
  7. Malignant Evaluation and Clinical Prognostic Values of M6A RNA Methylation Regulators in Prostate Cancer.
  8. N6-methyladenosine (m6A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer.
  9. DNA methylation regulator-mediated modification patterns and tumor microenvironment characterization in gastric cancer.
  1. Medicine (Baltimore). 2021 May 21. 100(20): e25952
    m6A regulators are associated with osteosarcoma metastasis and have prognostic significance: A study based on public databases.
    Wenpeng Zhang, Lina Wang, Ping Zhang, Quanbin Zhang.
       BACKGROUND: Osteosarcoma represents the most common malignant bone tumor with high metastatic potential and inferior prognosis. RNA methylation (N6-methyladenosine [m6A]) is a prevalent RNA modification that epigenetically influences numerous biological processes including tumorigenesis. This study aims to determine that m6A regulators are significant biomarkers for osteosarcoma, and establish a prognostic model to predict the survival of patients.
    METHODS: In this study, we comprehensively analyzed the underlying associations between m6A regulators' mRNA expressions and metastasis as well as prognosis of osteosarcoma patients in the Cancer Genome Atlas. Multivariate Cox-regression analysis was used to screen regulators that were significantly associated with overall survival of osteosarcoma patients. Least absolute shrinkage and selection operator (LASSO) Cox-regression analysis was used for constructing m6A regulator-based osteosarcoma prognostic signature.
    RESULTS: Some of the regulators exhibited aberrant mRNA levels between osteosarcoma samples with and without metastasis. Multivariate Cox-regression analysis identified several regulators with potential prognostic significance. A risk score formula consisted of methyltransferase-like 3, YTH domains of Homo sapiens, and fat mass and obesity-associated protein was obtained through which patients could be prognostically stratified independently of potential confounding factors. The signature was also significantly associated with the metastatic potential of osteosarcoma. All the analyses could be well reproduced in another independent osteosarcoma cohort from the Gene Expression Omnibus.
    CONCLUSIONS: In conclusion, this study first revealed potential roles of m6A regulators in osteosarcoma metastasis and prognosis, which should be helpful for its clinical decision-making.
    DOI:  https://doi.org/10.1097/MD.0000000000025952
  2. Biomark Res. 2021 May 17. 9(1): 36
    Functions of RNA N6-methyladenosine modification in acute myeloid leukemia.
    Xue Zheng, Yuping Gong.
      Acute myeloid leukemia (AML) is a hematologic malignancy with an unfavorable prognosis. A better understanding of AML pathogenesis and chemotherapy resistance at the molecular level is essential for the development of new therapeutic strategies. Apart from DNA methylation and histone modification, RNA epigenetic modification, another layer of epigenetic modification, also plays a critical role in gene expression regulation. Among the more than 150 kinds of RNA epigenetic modifications, N6-methyladenosine (m6A) is the most prevalent internal mRNA modification in eukaryotes and is involved in various biological processes, such as circadian rhythms, adipogenesis, T cell homeostasis, spermatogenesis, and the heat shock response. As a reversible and dynamic modification, m6A is deposited on specific target RNA molecules by methyltransferases and is removed by demethylases. Moreover, m6A binding proteins recognize m6A modifications, influencing RNA splicing, stability, translation, nuclear export, and localization at the posttranscriptional level. Emerging evidence suggests that dysregulation of m6A modification is involved in tumorigenesis, including that of AML. In this review, we summarize the most recent advances regarding the biological functions and molecular mechanisms of m6A RNA methylation in normal hematopoiesis, leukemia cell proliferation, apoptosis, differentiation, therapeutic resistance, and leukemia stem cell/leukemia initiating cell (LSC/LIC) self-renewal. In addition, we discuss how m6A regulators are closely correlated with the clinical features of AML patients and may serve as new biomarkers and therapeutic targets for AML.
    Keywords:  Acute myeloid leukemia; Epigenetics; N6-methyladenosine (m6A); RNA methylation
    DOI:  https://doi.org/10.1186/s40364-021-00293-w
  3. Cell Mol Gastroenterol Hepatol. 2021 May 13. pii: S2352-345X(21)00096-5. [Epub ahead of print]
    METTL3/METTL14 transactivation and m6A-dependent TGF-β1 translation in activated Kupffer cells.
    Yue Feng, Haibo Dong, Bo Sun, Yun Hu, Yang Yang, Yimin Jia, Longfei Jia, Xiang Zhong, Ruqian Zhao.
       BACKGROUND AND AIMS: Transforming growth factor-beta1 (TGF-β1) secreted from activated Kupffer cells (KC) promotes the progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis. N6-methyladenosine (m6A) RNA modification participates in various cell stress responses, yet it remains unknown whether it plays a role in TGF-β1 up-regulation in activated KC.
    METHODS: Western blot, Dot blot and LC-MS/MS were used to determine the expression of m6A methyltransferase, METTL3 and METTL14, as well as global m6A modification. RNA-seq and m6A-seq were employed to screen differentially expressed genes and responsive m6A peaks. NF-κB-mediated METTL3/METTL14 transactivation were validated with ChIP-PCR and dual-luciferase reporter system, and the role of m6A in TGF-β1 up-regulation was further verified in METTL3/METTL14-deficient KC and myeloid lineage cell-specific METTL14 knockout mice.
    RESULTS: Serum lipopolysaccharide (LPS) concentration is increased in high-fat diet induced NASH rats. TGF-β1 up-regulation is closely associated with METTL3/METTL14 up-regulation and global m6A hypermethylation, in both NASH rat liver and LPS-activated KC. LPS-responsive m6A peaks are identified on 5'UTR of TGF-β1 mRNA. NF-κB directly transactivate METTL3 and METTL14 genes. LPS-stimulated TGF-β1 expression is abolished in METTL3/METTL14-deficient KC and myeloid lineage cell-specific METTL14 knockout mice. Mutation of m6A sites on 5'UTR of TGF-β1 mRNA blocks LPS-induced increase of luciferase reporter activity.
    CONCLUSION: NF-κB acts as transcription factor to transactivate METTL3/METTL14 genes upon LPS challenge, leading to global RNA m6A hypermethylation. Increased m6A on 5'UTR of TGF-β1 mRNA results in m6A-dependent translation of TGF-β1 mRNA in a cap-independent manner. We identify a novel role of m6A modification in TGF-β1 up-regulation, which helps to shed light on the molecular mechanism of NASH progression.
    Keywords:  N6-methyladenosine; NASH; NF-κB; TGF-β1
    DOI:  https://doi.org/10.1016/j.jcmgh.2021.05.007
  4. Neoplasia. 2021 May 14. pii: S1476-5586(21)00022-1. [Epub ahead of print]23(6): 551-560
    Understanding the roles of N6-methyladenosine writers, readers and erasers in breast cancer.
    Runping Fang, Lihong Ye, Hui Shi.
      Breast cancer is believed to be driven by epigenetic regulation of genes implicated in cell proliferation, survival, and differentiation. Recently, aberrant N6-methyladenosine (m6A) decorations turned up as crucial epigenetic regulator for malignant breast cancer, which may serve as new targets for breast cancer treatment. Here we briefly outline the functions of m6A and its regulatory proteins, including m6A "writers," "readers," and "erasers" on RNA life fate, recapitulate the latest breakthroughs in understanding m6A modification and its regulatory proteins, and the underlying molecular mechanisms that contribute to the carcinogenesis and the progression of breast cancer, so as to provide potential epigenetic targets for diagnosis, treatment and prognosis in breast cancer.
    Keywords:  Breast cancer; Demethylase; Epigenetics; Methyltransferase; m(6)A modification; m(6)A reader
    DOI:  https://doi.org/10.1016/j.neo.2021.04.002
  5. Cell Death Dis. 2021 May 20. 12(6): 518
    Suppression of m6A mRNA modification by DNA hypermethylated ALKBH5 aggravates the oncological behavior of KRAS mutation/LKB1 loss lung cancer.
    Donghong Zhang, Jinfeng Ning, Imoh Okon, Xiaoxu Zheng, Ganesh Satyanarayana, Ping Song, Shidong Xu, Ming-Hui Zou.
      Oncogenic KRAS mutations combined with the loss of the LKB1 tumor-suppressor gene (KL) are strongly associated with aggressive forms of lung cancer. N6-methyladenosine (m6A) in mRNA is a crucial epigenetic modification that controls cancer self-renewal and progression. However, the regulation and role of m6A modification in this cancer are unclear. We found that decreased m6A levels correlated with the disease progression and poor survival for KL patients. The correlation was mediated by a special increase in ALKBH5 (AlkB family member 5) levels, an m6A demethylase. ALKBH5 gain- or loss-of function could effectively reverse LKB1 regulated cell proliferation, colony formation, and migration of KRAS-mutated lung cancer cells. Mechanistically, LKB1 loss upregulated ALKBH5 expression by DNA hypermethylation of the CTCF-binding motif on the ALKBH5 promoter, which inhibited CTCF binding but enhanced histone modifications, including H3K4me3, H3K9ac, and H3K27ac. This effect could successfully be rescued by LKB1 expression. ALKBH5 demethylation of m6A stabilized oncogenic drivers, such as SOX2, SMAD7, and MYC, through a pathway dependent on YTHDF2, an m6A reader protein. The above findings were confirmed in clinical KRAS-mutated lung cancer patients. We conclude that loss of LKB1 promotes ALKBH5 transcription by a DNA methylation mechanism, reduces m6A modification, and increases the stability of m6A target oncogenes, thus contributing to aggressive phenotypes of KRAS-mutated lung cancer.
    DOI:  https://doi.org/10.1038/s41419-021-03793-7
  6. Cancer Cell. 2021 May 11. pii: S1535-6108(21)00224-5. [Epub ahead of print]
    The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth.
    Lihui Dong, Chuanyuan Chen, Yawei Zhang, Peijin Guo, Zhenghang Wang, Jian Li, Yi Liu, Jun Liu, Renbao Chang, Yilin Li, Guanghao Liang, Weiyi Lai, Mengxue Sun, Urszula Dougherty, Marc B Bissonnette, Hailin Wang, Lin Shen, Meng Michelle Xu, Dali Han.
      Tumor-associated macrophages (TAMs) can dampen the antitumor activity of T cells, yet the underlying mechanism remains incompletely understood. Here, we show that C1q+ TAMs are regulated by an RNA N6-methyladenosine (m6A) program and modulate tumor-infiltrating CD8+ T cells by expressing multiple immunomodulatory ligands. Macrophage-specific knockout of an m6A methyltransferase Mettl14 drives CD8+ T cell differentiation along a dysfunctional trajectory, impairing CD8+ T cells to eliminate tumors. Mettl14-deficient C1q+ TAMs show a decreased m6A abundance on and a higher level of transcripts of Ebi3, a cytokine subunit. In addition, neutralization of EBI3 leads to reinvigoration of dysfunctional CD8+ T cells and overcomes immunosuppressive impact in mice. We show that the METTL14-m6A levels are negatively correlated with dysfunctional T cell levels in patients with colorectal cancer, supporting the clinical relevance of this regulatory pathway. Thus, our study demonstrates how an m6A methyltransferase in TAMs promotes CD8+ T cell dysfunction and tumor progression.
    Keywords:  EBI3; METTL14; T cell dysfunction; m(6)A epi-transcriptome; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.ccell.2021.04.016
  7. J Cancer. 2021 ;12(12): 3575-3586
    Malignant Evaluation and Clinical Prognostic Values of M6A RNA Methylation Regulators in Prostate Cancer.
    Qijie Zhang, Jiaochen Luan, Lebin Song, Xiyi Wei, Jiadong Xia, Ninghong Song.
      Objective: M6A RNA modification is closely associated with tumor genesis and progression of several malignancies; however, its role in prostate cancer (PCa) remains poorly understood. Materials and methods: Expression data and corresponding clinicopathologic information were available freely from the Cancer Genome Atlas (TCGA) dataset. We compared the expression level of m6A RNA methylation regulators in PCa with different clinicopathologic characteristics and identified subgroups based on their expressions with consensus clustering. To build the signature and assess its prognostic value, several methods were used for the analysis, including univariate Cox regression analysis, Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, time-dependent receiver operating curve (ROC), and Kaplan-Meier (KM) survival analysis. Results: Most of the m6A RNA methylation regulators were differentially expressed not only between normal and tumor tissue but also among PCa stratified by different clinicopathologic characteristics. There were obvious differences between two clusters, cluster 1 and 2, regarding clinicopathologic features, and the recurrence-free survival (RFS) in cluster 2 was significantly worse than cluster 1. We developed an eleven-gene signature which exhibited a high prognostic value and was able to independently predict RFS. Moreover, a nomogram which integrated clinical information and the gene signature was capable of distinguishing high-risk recurrent patients. Conclusion: These methylation regulators are correlated to clinicopathologic characteristics in PCa and a prognostic model using m6A methylation-related genes is constructed and of high predictive value for recurrence after RP.
    Keywords:  gene signature.; m6A RNA methylation; prognosis; prostate cancer
    DOI:  https://doi.org/10.7150/jca.55140
  8. Cell Death Discov. 2021 May 17. 7(1): 108
    N6-methyladenosine (m6A) methyltransferase KIAA1429 accelerates the gefitinib resistance of non-small-cell lung cancer.
    Jun Tang, Tianci Han, Wei Tong, Jian Zhao, Wei Wang.
      N6-methyladenosine (m6A) modification has been convincingly identified to be a critical regulator in human cancer. However, the contribution of m6A to NSCLC gefitinib resistance is still largely unknown. Here, we screened and identified that m6A methyltransferase KIAA1429 was highly expressed in gefitinib-resistant NSCLC cells (PC9-GR), tissues, and closely related to unfavorable survival. Functionally, KIAA1429 accelerated the gefitinib resistance of NSCLC in vitro. Depletion of KIAA1429 repressed the tumor growth of PC9-GR cells in vivo. Mechanistically, KIAA1429 enhanced the mRNA stability of HOXA1 through targeting its 3'-untranslated regions (3'-UTR). Overall, our findings indicate that KIAA1429 plays essential oncogenic roles in NSCLC gefitinib resistance, which may provide a feasible therapeutic target for NSCLC.
    DOI:  https://doi.org/10.1038/s41420-021-00488-y
  9. Mol Ther Nucleic Acids. 2021 Jun 04. 24 695-710
    DNA methylation regulator-mediated modification patterns and tumor microenvironment characterization in gastric cancer.
    Qi Meng, Yun-Xin Lu, Dan-Yun Ruan, Kai Yu, Yan-Xing Chen, Min Xiao, Yun Wang, Ze-Xian Liu, Rui-Hua Xu, Huai-Qiang Ju, Miao-Zhen Qiu.
      Growing evidence implies a link between DNA methylation and tumor immunity/immunotherapy. However, the global influence of DNA methylation on the characteristics of the tumor microenvironment and the efficacy of immunotherapy remains to be clarified. In this study, we systematically evaluated the DNA methylation regulator patterns and tumor microenvironment characteristics of 1,619 gastric cancer patients by clustering the gene expression of 20 DNA methylation regulators. Three gastric cancer subtypes that had different DNA methylation modification patterns and distinct tumor microenvironment characteristics were recognized. Then, a DNA methylation score (DMS) was constructed to evaluate DNA methylation modification individually. High DMS was characterized by immune activation status, increased tumor mutation burden, and tumor neoantigens, with a favorable prognosis. Conversely, activation of the stroma and absence of immune cell infiltration were observed in the low DMS group, with relatively poor survival. High DMS was also certified to be correlated with enhanced efficacy of immunotherapy in four immune checkpoint blocking treatment cohorts. In conclusion, the characterization of DNA methylation modification patterns may help to enhance our recognition of the tumor immune microenvironment of gastric cancer and guide more personalized immunotherapy strategies in the future.
    Keywords:  DNA methylation; biomarker; gastric cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.omtn.2021.03.023
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