bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–05–29
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Upregulation of METTL14 contributes to trophoblast dysfunction by elevating FOXO3a expression in an m6A-dependent manner.
  2. A novel signature based on m6A RNA methylation regulators reveals distinct prognostic subgroups and associates with tumor immunity of patients with pancreatic neuroendocrine neoplasms.
  3. Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway.
  4. Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA.
  5. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents HCC recurrence after radiofrequency ablation.
  6. Prognostic score model based on six m6A-related autophagy genes for predicting survival in esophageal squamous cell carcinoma.
  7. N6-Methyladenosine-Related lncRNAs Are Novel Prognostic Markers and Predict the Immune Landscape in Acute Myeloid Leukemia.
  8. Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma.
  1. Placenta. 2022 May 14. pii: S0143-4004(22)00246-6. [Epub ahead of print]124 18-27
    Upregulation of METTL14 contributes to trophoblast dysfunction by elevating FOXO3a expression in an m6A-dependent manner.
    Wenqiang Fan, Wenbo Zhou, Qiang Yan, Yue Peng, Huiyan Wang, Chengcai Kong, Bin Zhang, Bin Yu, Li Chen, Pingping Xue.
       INTRODUCTION: Preeclampsia, a specific complication of pregnancy, is a leading cause of perinatal and maternal mortality worldwide. N6-methyladenosine (m6A) is a prevalent and reversible modification of mammalian mRNAs, and is known to play an important role in various physiological and pathological processes. However, little is known about its possible effects on trophoblasts in preeclampsia.
    METHODS: Colorimetric RNA m6A methylation quantification assay and dot blotting were used to assess the levels of global RNA m6A modification in placental tissues collected from females with normal pregnancy and preeclampsia, while the mRNA levels of major m6A methyltransferases/demethylases were investigated by quantitative real-time polymerase chain reaction. The effects of methyltransferase-like 14 (METTL14) on trophoblasts were evaluated using cell counting kit-8, transwell invasion assay, autophagic flux assay, and Annexin V/propidium iodide apoptosis assay. The molecular mechanism underlying the regulation of forkhead box O3a (FOXO3a) expression by METTL14 was determined using methylated RNA immunoprecipitation and transcription inhibition assays.
    RESULTS: Global RNA m6A methylation and METTL14 expression were significantly increased in placental tissues obtained from patients with preeclampsia. In vitro studies showed that overexpression of METTL14 in HTR-8/SVneo cells inhibited trophoblast proliferation and invasion, but induced trophoblast autophagy and apoptosis. We further demonstrated that METTL14 epigenetically elevated FOXO3a expression via an m6A-dependent mechanism. FOXO3a inhibition effectively prevented the impairment of trophoblast proliferation and invasion, and diminished the induction of trophoblast autophagy and apoptosis in METTL14-overexpressing HTR-8/SVneo cells.
    DISCUSSION: Increased METTL14-mediated m6A modification results in an adverse impact on trophoblast function by elevating FOXO3a expression.
    Keywords:  FOXO3a; METTL14; Preeclampsia; Trophoblast cells; m(6)A methylation
    DOI:  https://doi.org/10.1016/j.placenta.2022.05.008
  2. Neuroendocrinology. 2022 May 24.
    A novel signature based on m6A RNA methylation regulators reveals distinct prognostic subgroups and associates with tumor immunity of patients with pancreatic neuroendocrine neoplasms.
    Xianlong Chen, Shengwei Mo, Liju Zong, Shuangni Yu, Zhaohui Lu, Jie Chen.
       INTRODUCTION: The RNA N6-methyladenosine (m6A) regulators play a crucial role in tumorigenesis and could be indicators of prognosis and therapeutic targets in various cancers. However, the expression status and prognostic value of m6A regulators have not been studied in pancreatic neuroendocrine neoplasms (PanNENs). We aimed to investigate the expression patterns and prognostic value of m6A regulators and assess their correlations with immune checkpoints and infiltrates in PanNENs.
    METHODS: Immunohistochemistry was performed for 15 m6A regulators and immune markers using tissue microarrays obtained from 183 patients with PanNENs. The correlation between m6A protein expression and clinicopathological parameters with recurrence-free survival (RFS) was examined using a random survival forest, Cox regression model and survival tree analysis.
    RESULTS: Among the 15 m6A proteins, high expression of YTHDF2 and HNRNPC was found to be significantly associated with recurrence and served as independent risk factors. High YTHDF2 expression was associated with higher number of CD3+ T cells, whereas high HNRNPC expression was significantly correlated with the expression of PD-L1. A YTHDF2-based signature was determined, including five patterns from survival tree analysis: patients with the LNnegYTHDF2high signature had a 5-year RFS rate of 92.1%, whereas patients with LNposTumorSize＜2.5cm signature had the worst 5-year RFS rate of 0%. The area under receiver operating characteristic curve was 0.870 for the YTHDF2-based signature. The C-index was 0.978, suggesting good discrimination ability; the risk score of recurrence served as an independent prognostic factor indicating shorter RFS.
    CONCLUSIONS: YTHDF2 appears to serve as a promising prognostic biomarker and therapeutic target. A YTHDF2-based signature can identify distinct subgroups, which may be helpful to strategize personalized postoperative monitoring.
    DOI:  https://doi.org/10.1159/000525228
  3. Cell Mol Life Sci. 2022 May 22. 79(6): 311
    Mettl14 mediates the inflammatory response of macrophages in atherosclerosis through the NF-κB/IL-6 signaling pathway.
    Yang Zheng, Yunqi Li, Xianwen Ran, Di Wang, Xianghui Zheng, Maomao Zhang, Bo Yu, Yong Sun, Jian Wu.
      The inflammatory response of macrophages has been reported to play a critical role in atherosclerosis. The inflammatory state of macrophages is modified by epigenetic reprogramming. m6A RNA methylation is an epigenetic modification of RNAs. However, little is known about the potential roles and underlying mechanisms of m6A modification in macrophage inflammation. Herein, we showed that the expression of the m6A modification "writer" Mettl14 was increased in coronary heart disease and LPS-stimulated THP-1 cells. Knockdown of Mettl14 promoted M2 polarization of macrophages, inhibited foam cell formation and decreased migration. Mechanistically, the expression of Myd88 and IL-6 was decreased in Mettl14 knockdown cells. Through m6A modification, Mettl14 regulated the stability of Myd88 mRNA. Furthermore, Myd88 affected the transcription of IL-6 via the distribution of p65 in nuclei rather than directly regulating the expression of IL-6 through m6A modification. In vivo, Mettl14 gene knockout significantly reduced the inflammatory response of macrophages and the development of atherosclerotic plaques. Taken together, our data demonstrate that Mettl14 plays a vital role in macrophage inflammation in atherosclerosis via the NF-κB/IL-6 signaling pathway, suggesting that Mettl14 may be a promising therapeutic target for the clinical treatment of atherosclerosis.
    Keywords:  Atherosclerosis; Inflammatory response; Macrophage; Mettl14; m6A modification
    DOI:  https://doi.org/10.1007/s00018-022-04331-0
  4. Biochemistry. 2022 May 23.
    Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA.
    Dan Yu, Jujun Zhou, Qin Chen, Tao Wu, Robert M Blumenthal, Xing Zhang, Xiaodong Cheng.
      PCIF1 and FTO are a pair of human mRNA cap-specific modification enzymes that have opposing activities. PCIF1 adds a methyl group to the N6-position of 2'O-methyladenosine (Am), generating N6, 2'O-dimethyladenosine (m6Am), when Am is the cap-proximal nucleotide. FTO removes the N6-methyl group from m6Am. In addition, FTO has a demethylase activity on a broad spectrum of various RNA substrates, as well as on DNA N6-methyldeoxyadenosine (m6dA). While the existence of m6dA in mammalian DNA remains controversial, we show here that PCIF1 has significant methylation activity on single stranded DNA deoxyadenosine, double stranded RNA/DNA hybrids, and double stranded DNA, though with lower catalytic efficiency than that on its preferred RNA substrate. PCIF1 has activities in the order ssRNA > RNA/DNA hybrid > ssDNA > dsDNA. We discuss the implications of PCIF1 generation, and FTO removal, of DNA adenine methylation.
    DOI:  https://doi.org/10.1021/acs.biochem.2c00134
  5. Hepatology. 2022 May 22.
    Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents HCC recurrence after radiofrequency ablation.
    Xuezhen Zeng, Guanrui Liao, Shumin Li, Haining Liu, Xiao Zhao, Shuang Li, Kai Lei, Shenghua Zhu, Zhihang Chen, Yi Zhao, Xuxin Ren, Tianhong Su, Alfred Sze-Lok Cheng, Sui Peng, Shuibin Lin, Ji Wang, Shuling Chen, Ming Kuang.
       BACKGROUND AND AIMS: Radiofrequency ablation (RFA) is an important curative therapy in hepatocellular carcinoma (HCC), but recurrence rate remains high as all the other HCC therapeutic modalities. Methyltransferase 1 (METTL1), an enzyme for m7 G tRNA modification, was reported to promote HCC development. Here, we assessed the role of METTL1 in shaping the immunosuppressive tumor microenvironment after insufficient RFA (iRFA).
    APPROACH AND RESULTS: By IHC and multiplex immunofluorescence (mIF) staining, we showed that METTL1 expression was enhanced in post-RFA recurrent HCC, accompanied by increased CD11b+ CD15+ PMN-MDSCs and decreased CD8+ T cells. Mechanistically, heat-mediated METTL1 upregulation enhanced TGF-β2 translation to form the immunosuppressive environment by induction of MDSC. Liver specific overexpression or knockout of Mettl1 significantly affected the accumulation of PMN-MDSCs and subsequently affected CD8+ T cell infiltration. Complete RFA (cRFA) successfully eliminated the tumor, while iRFA-treated mice exhibited enhanced tumor growth and metastasis with increased PMN-MDSC accumulation and decreased CD8+ T cells compared to sham surgery. Interrupting METTL1-TGF-β2-PMN-MDSC axis by anti-Ly6G antibody, or knockdown of hepatoma-intrinsic Mettl1 or Tgfb2, or TGF-β signaling blockade significantly mitigated tumor progression induced by iRFA and restored CD8+ T cell population.
    CONCLUSIONS: Our study sheds light on a previsouly unrevealed role of METTL1 in modulating an immunosuppressive microenvironment, and demonstrated that interrupting METTL1- TGF-β2-PMN-MDSC axis could be a novel therapeutic strategy to restore anti-tumor immunity and prevent HCC recurrence after RFA treatment, meriting further clinical studies.
    DOI:  https://doi.org/10.1002/hep.32585
  6. J Clin Lab Anal. 2022 May 25. e24507
    Prognostic score model based on six m6A-related autophagy genes for predicting survival in esophageal squamous cell carcinoma.
    Funan Chen, Erxiu Gong, Jun Ma, Jiehuan Lin, Canxing Wu, Shanshan Chen, Shuqiao Hu.
       BACKGROUND: Prognostic signatures based on autophagy genes have been proposed for esophageal squamous cell carcinoma (ESCC). Autophagy genes are closely associated with m6A genes. Our purpose is to identify m6A-related autophagy genes in ESCC and develop a survival prediction model.
    METHODS: Differential expression analyses for m6A genes and autophagy genes were performed based on TCGA and HADd databases followed by constructing a co-expression network. Uni-variable Cox regression analysis was performed for m6A-related autophagy genes. Using the optimal combination of feature genes by LASSO Cox regression model, a prognostic score (PS) model was developed and subsequently validated in an independent dataset.
    RESULTS: The differential expression of 13 m6A genes and 107 autophagy genes was observed between ESCC and normal samples. The co-expression network contained 13 m6A genes and 96 autophagy genes. Of the 12 m6A-related autophagy genes that were significantly related to survival, DAPK2, DIRAS3, EIF2AK3, ITPR1, MAP1LC3C, and TP53 were used to construct a PS model, which split the training set into two risk groups with significant different survival ratios (p = 0.015, 1-year, 3-year, and 5-year AUC = 0.873, 0.840, and 0.829). Consistent results of GSE53625 dataset confirmed predictive ability of the model (p = 0.024, 1-year, 3-year, and 5-year AUC = 0.793, 0.751, and 0.744). The six-gene PS score was an independent prognostic factor from clinical factors (HR, 2.362; 95% CI, 1.390-7.064; p-value = 0.012).
    CONCLUSION: Our study recommends 6 m6A-related autophagy genes as promising prognostic biomarkers and develops a PS model to predict survival in ESCC.
    Keywords:  autophagy; co-expression network; m6A methylation; prognostic score
    DOI:  https://doi.org/10.1002/jcla.24507
  7. Front Genet. 2022 ;13 804614
    N6-Methyladenosine-Related lncRNAs Are Novel Prognostic Markers and Predict the Immune Landscape in Acute Myeloid Leukemia.
    Lulu Zhang, Wen Ke, Pin Hu, Zhangzhi Li, Wei Geng, Yigang Guo, Bin Song, Hua Jiang, Xia Zhang, Chucheng Wan.
      Background: Acute myelocytic leukemia (AML) is one of the hematopoietic cancers with an unfavorable prognosis. However, the prognostic value of N 6-methyladenosine-associated long non-coding RNAs (lncRNAs) in AML remains elusive. Materials and Methods: The transcriptomic data of m6A-related lncRNAs were collected from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. AML samples were classified into various subgroups according to the expression of m6A-related lncRNAs. The differences in terms of biological function, tumor immune microenvironment, copy number variation (CNV), and drug sensitivity in AML between distinct subgroups were investigated. Moreover, an m6A-related lncRNA prognostic model was established to evaluate the prognosis of AML patients. Results: Nine prognosis-related m6A-associated lncRNAs were selected to construct a prognosis model. The accuracy of the model was further determined by the Kaplan-Meier analysis and time-dependent receiver operating characteristic (ROC) curve. Then, AML samples were classified into high- and low-risk groups according to the median value of risk scores. Gene set enrichment analysis (GSEA) demonstrated that samples with higher risks were featured with aberrant immune-related biological processes and signaling pathways. Notably, the high-risk group was significantly correlated with an increased ImmuneScore and StromalScore, and distinct immune cell infiltration. In addition, we discovered that the high-risk group harbored higher IC50 values of multiple chemotherapeutics and small-molecule anticancer drugs, especially TW.37 and MG.132. In addition, a nomogram was depicted to assess the overall survival (OS) of AML patients. The model based on the median value of risk scores revealed reliable accuracy in predicting the prognosis and survival status. Conclusion: The present research has originated a prognostic risk model for AML according to the expression of prognostic m6A-related lncRNAs. Notably, the signature might also serve as a novel biomarker that could guide clinical applications, for example, selecting AML patients who could benefit from immunotherapy.
    Keywords:  acute myeloid leukemia; copy number variation; immune infiltration; long non-coding RNA; m6A modification; prognosis
    DOI:  https://doi.org/10.3389/fgene.2022.804614
  8. Adv Sci (Weinh). 2022 May 26. e2105120
    Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma.
    Deepak Kumar, Manasi Das, Alexis Oberg, Debashis Sahoo, Panyisha Wu, Consuelo Sauceda, Lily Jih, Lesley G Ellies, Magda T Langiewicz, Supriya Sen, Nicholas J G Webster.
      Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.
    Keywords:  RNA splicing; insulin-like growth factor; liver cancer; prognosis
    DOI:  https://doi.org/10.1002/advs.202105120
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