bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–02–28
nine papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. The role of m6A modification in the biological functions and diseases.
  2. Identification of a Two-m6A RNA Methylation Regulator Risk Signature as an Independent Prognostic Biomarker in Papillary Renal Cell Carcinoma by Bioinformatic Analysis.
  3. Identification of a New Prognostic Risk Signature of Clear Cell Renal Cell Carcinoma Based on N6-Methyladenosine RNA Methylation Regulators.
  4. Aberrant expression of m6A mRNA methylation regulators in colorectal adenoma and adenocarcinoma.
  5. HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.
  6. The role of RNA N 6-methyladenosine methyltransferase in cancers.
  7. FTO modifies the m6A level of MALAT and promotes bladder cancer progression.
  8. N6-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles.
  9. Prognostic Roles of N6-Methyladenosine METTL3 in Different Cancers: A System Review and Meta-Analysis.
  1. Signal Transduct Target Ther. 2021 Feb 21. 6(1): 74
    The role of m6A modification in the biological functions and diseases.
    Xiulin Jiang, Baiyang Liu, Zhi Nie, Lincan Duan, Qiuxia Xiong, Zhixian Jin, Cuiping Yang, Yongbin Chen.
      N6-methyladenosine (m6A) is the most prevalent, abundant and conserved internal cotranscriptional modification in eukaryotic RNAs, especially within higher eukaryotic cells. m6A modification is modified by the m6A methyltransferases, or writers, such as METTL3/14/16, RBM15/15B, ZC3H3, VIRMA, CBLL1, WTAP, and KIAA1429, and, removed by the demethylases, or erasers, including FTO and ALKBH5. It is recognized by m6A-binding proteins YTHDF1/2/3, YTHDC1/2 IGF2BP1/2/3 and HNRNPA2B1, also known as "readers". Recent studies have shown that m6A RNA modification plays essential role in both physiological and pathological conditions, especially in the initiation and progression of different types of human cancers. In this review, we discuss how m6A RNA methylation influences both the physiological and pathological progressions of hematopoietic, central nervous and reproductive systems. We will mainly focus on recent progress in identifying the biological functions and the underlying molecular mechanisms of m6A RNA methylation, its regulators and downstream target genes, during cancer progression in above systems. We propose that m6A RNA methylation process offer potential targets for cancer therapy in the future.
    DOI:  https://doi.org/10.1038/s41392-020-00450-x
  2. Biomed Res Int. 2021 ;2021 4582082
    Identification of a Two-m6A RNA Methylation Regulator Risk Signature as an Independent Prognostic Biomarker in Papillary Renal Cell Carcinoma by Bioinformatic Analysis.
    Feilong Yang, Guojiang Zhao, Liyuan Ge, Yimeng Song, Kai Hong, Hongxian Zhang, Cheng Liu, Peng Hong, Lulin Ma.
      N6-Methyladenosine (m6A), the most common form of mRNA modification, is dynamically regulated by the m6A RNA methylation regulators, which play an important role in regulating the gene expression and phenotype in both health and disease. However, the role of m6A in papillary renal cell carcinoma (pRCC) is unknown. The purpose of this work is to investigate the prognostic value of m6A RNA methylation regulators in pRCC; thus, we can build a risk score model based on m6A RNA methylation regulators as a risk signature for predicting the prognosis of pRCC. Here, we investigated the expression and corresponding clinical data by bioinformatic analysis based on 289 pRCC tissues and 32 normal kidney tissues obtained from TCGA database. As a result, we identified the landscape of m6A RNA methylation regulators in pRCC. We grouped all pRCC patients into two clusters by consensus clustering to m6A RNA methylation regulators, but we found that the clusters were not correlated to the prognosis and clinicopathological features of pRCC. Therefore, we additionally built a two-m6A RNA methylation regulator risk score model as a risk signature by the univariate Cox regression analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. The risk signature was constructed as follows: 0.031HNRNPC + 0.199KIAA1429. It revealed that the risk score was associated with the clinicopathological features such as pT status and pN status of pRCC. More importantly, the risk score was an independent prognostic marker for pRCC patients. Thus, m6A RNA methylation regulators contributed to the malignant progression of pRCC influencing its prognosis.
    DOI:  https://doi.org/10.1155/2021/4582082
  3. J Immunol Res. 2021 ;2021 6617841
    Identification of a New Prognostic Risk Signature of Clear Cell Renal Cell Carcinoma Based on N6-Methyladenosine RNA Methylation Regulators.
    Yan Zhang, Yao Yao, Xiaochen Qi, Jianyi Li, Meihong Liu, Xiangyu Che, Yingkun Xu, Guangzhen Wu.
      As the most prevalent internal eukaryotic modification, N6-methyladenosine (m6A) is installed by methyltransferases, removed by demethylases, and recognized by readers. However, there are few studies on the role of m6A in clear cell renal cell carcinoma (ccRCC). In this study, we researched the RNA-seq transcriptome data of ccRCC in the TCGA dataset and used bioinformatics analyses to detect the relationship between m6A RNA methylation regulators and ccRCC. First, we compared the expression of 18 m6A RNA methylation regulators in ccRCC patients and normal tissues. Then, data from ccRCC patients were divided into two clusters by consensus clustering. LASSO Cox regression analysis was used to build a risk signature to predict the prognosis of patients with ccRCC. An ROC curve, univariate Cox regression analysis, and multivariate Cox regression analysis were used to verify this risk signature's predictive ability. Then, we internally validated this signature by random sampling. Finally, we explored the role of the genes in the signature in some common pathways. Gene distribution between the two subgroups was different; cluster 2 was gender-related and had a worse prognosis. IGF2BP3, IGF2BP2, HNRNPA2B1, and METTL14 were chosen to build the risk signature. The overall survival of the high- and low-risk groups was significantly different (p = 7.47e - 12). The ROC curve also indicated that the risk signature had a decent predictive significance (AUC = 0.72). These results imply that the risk signature has a potential value for ccRCC treatment.
    DOI:  https://doi.org/10.1155/2021/6617841
  4. Life Sci. 2021 Feb 23. pii: S0024-3205(21)00243-5. [Epub ahead of print] 119258
    Aberrant expression of m6A mRNA methylation regulators in colorectal adenoma and adenocarcinoma.
    Dayu Kuai, Shengtao Zhu, Haiyun Shi, Ruichuang Yang, Tong Liu, Hui Liu, Li Min, Shutian Zhang.
       BACKGROUND: As the most prevalent post-transcriptional mRNA modification in eukaryotes, N6-Methyladenosine (m6A) is closely linked to the occurrence and development of colorectal cancer (CRC). However, there is no systematic evaluation of the expression of m6A regulatory genes in CRC.
    METHODS: By analyzing the TCGA database, we identified METTL3, YTHDF1, IGF2BP1, IGF2BP3, EIF3B, HNRNPA2B1 as overexpressed m6A regulators in CRC. After verification by immunohistochemistry (IHC) in 10 CRC cases, YTHDF1, IGF2BP1, IGF2BP3, and EIF3B were identified as potential biomarkers in CRC. Further validation was done by IHC and qRT-PCR in two larger cohorts.
    RESULTS: We identified 6 up-regulated m6A regulatory genes in CRC in TCGA analysis, and verified that YTHDF1, IGF2BP1, IGF2BP3, and EIFB3 were all significantly differentially expressed between CRC and normal tissues by IHC (p < 0.0001). In another larger cohort, we further validated the overexpression of those genes in CRC as compared to both normal tissues (p < 0.0001) and adenoma tissues (p < 0.05). Detailed analysis suggested that detection of one of the three genes, YTHDF1, IGF2BP1 and IGF2BP3, and combined detection of EIF3B gene could be a good strategy for early diagnosis of both CRC and precancerous lesions. Furthermore, we found that the mRNA levels of YTHDF1, IGF2BP1, and IGF2BP3 were also significantly up-regulated in CRC but not adenoma as compared to normal tissues.
    CONCLUSION: We evaluted the abnormal expression of m6A regulatory genes during CRC carcinogenesis, and identified four m6A genes (YTHDF1, IGF2BP1, IGF2BP3, and EIF3B) as potential biomarkers of both CRC and adenoma.
    Keywords:  Biomarkers; CRC; m(6)A regulators
    DOI:  https://doi.org/10.1016/j.lfs.2021.119258
  5. Signal Transduct Target Ther. 2021 Feb 23. 6(1): 76
    HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation.
    Qing Li, Yong Ni, Liren Zhang, Runqiu Jiang, Jing Xu, Hong Yang, Yuanchang Hu, Jiannan Qiu, Liyong Pu, Jinhai Tang, Xuehao Wang.
      N6-methyladenosine (m6A), and its reader protein YTHDF1, play a pivotal role in human tumorigenesis by affecting nearly every stage of RNA metabolism. Autophagy activation is one of the ways by which cancer cells survive hypoxia. However, the possible involvement of m6A modification of mRNA in hypoxia-induced autophagy was unexplored in human hepatocellular carcinoma (HCC). In this study, specific variations in YTHDF1 expression were detected in YTHDF1-overexpressing, -knockout, and -knockdown HCC cells, HCC organoids, and HCC patient-derived xenograft (PDX) murine models. YTHDF1 expression and hypoxia-induced autophagy were significantly correlated in vitro; significant overexpression of YTHDF1 in HCC tissues was associated with poor prognosis. Multivariate cox regression analysis identified YTHDF1 expression as an independent prognostic factor in patients with HCC. Multiple HCC models confirmed that YTHDF1 deficiency inhibited HCC autophagy, growth, and metastasis. Luciferase reporter assays and chromatin immunoprecipitation demonstrated that HIF-1α regulated YTHDF1 transcription by directly binding to its promoter region under hypoxia. The results of methylated RNA immunoprecipitation sequencing, proteomics, and polysome profiling indicated that YTHDF1 contributed to the translation of autophagy-related genes ATG2A and ATG14 by binding to m6A-modified ATG2A and ATG14 mRNA, thus facilitating autophagy and autophagy-related malignancy of HCC. Taken together, HIF-1α-induced YTHDF1 expression was associated with hypoxia-induced autophagy and autophagy-related HCC progression via promoting translation of autophagy-related genes ATG2A and ATG14 in a m6A-dependent manner. Our findings suggest that YTHDF1 is a potential prognostic biomarker and therapeutic target for patients with HCC.
    DOI:  https://doi.org/10.1038/s41392-020-00453-8
  6. Mol Ther Nucleic Acids. 2021 Mar 05. 23 887-896
    The role of RNA N 6-methyladenosine methyltransferase in cancers.
    Jiali Huang, Zhenyao Chen, Xin Chen, Jun Chen, Zhixiang Cheng, Zhaoxia Wang.
      Modification of eukaryotic RNA by methylation of adenosine residues to generate N 6-methyladenosine (m6A) is a highly prevalent process. m6A is dynamically regulated during cell metabolism and embryo development, and it is mainly involved in various aspects of RNA metabolism, including RNA splicing, processing, transport from the nucleus, translation, and degradation. Accumulating evidence shows that dynamic changes to m6A are closely related to the occurrence and development of cancer and that methyltransferases, as key elements in the dynamic regulation of m6A, play a crucial role in these processes. Therefore, in this review, we describe the role of methyltransferases as m6A writers in cancer and summarize their potential molecular mechanisms of action.
    Keywords:  METTL14; METTL3; RNA; WTAP; cancer; m6A; methyltransferase
    DOI:  https://doi.org/10.1016/j.omtn.2020.12.021
  7. Clin Transl Med. 2021 Feb;11(2): e310
    FTO modifies the m6A level of MALAT and promotes bladder cancer progression.
    Le Tao, Xingyu Mu, Haige Chen, Di Jin, Ruiyun Zhang, Yuyang Zhao, Jie Fan, Ming Cao, Zhihua Zhou.
       BACKGROUND: Nearly a half million people around the world are diagnosed with bladder cancer each year, and an incomplete understanding of its pathogenicity and lack of efficient biomarkers having been discovered lead to poor clinical management of bladder cancer. Fat mass and obesity-associated protein (FTO) is a critical player in carcinogenesis. We, here, explored the role of FTO and unraveled the mechanism of its function in bladder cancer.
    METHODS: Identification of the correlation of FTO with bladder cancer was based on both bioinformatics and clinical analysis of tissue samples collected from a cohort of patients at a hospital and microarray data. Gain-of-function and loss-of-function assays were conducted in vivo and in vitro to assess the effect of FTO on bladder carcinoma tumor growth and its impact on the bladder carcinoma cell viability. Moreover, the interactions of intermediate products were also investigated to elucidate the mechanisms of FTO function.
    RESULTS: Bladder tumor tissues had increased FTO expression which correlated with clinical bladder cancer prognosis and outcomes. Both in vivo and in vitro, it played the function of an oncogene in stimulating the cell viability and tumorigenicity of bladder cancer. Furthermore, FTO catalyzed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) demethylation, regulated microRNA miR-384 and mal T cell differentiation protein 2 (MAL2) expression, and modulated the interactions among these processes.
    CONCLUSIONS: The interplay of these four clinically relevant factors contributes to the oncogenesis of bladder cancer. FTO facilitates the tumorigenesis of bladder cancer through regulating the MALAT/miR-384/MAL2 axis in m6A RNA modification manner, which ensures the potential of FTO for serving as a diagnostic or prognostic biomarker in bladder cancer.
    Keywords:  FTO; MAL2; MALAT1; N6-methyladenosine mRNA modification; bladder cancer; cell viability; miR-384; tumor growth
    DOI:  https://doi.org/10.1002/ctm2.310
  8. Dev Cell. 2021 Feb 15. pii: S1534-5807(21)00073-3. [Epub ahead of print]
    N6-methyladenosine modification of MALAT1 promotes metastasis via reshaping nuclear speckles.
    Xinyu Wang, Chong Liu, Siwei Zhang, Huiwen Yan, Liwen Zhang, Amin Jiang, Yong Liu, Yun Feng, Di Li, Yuting Guo, Xinyao Hu, Yajing Lin, Pengcheng Bu, Dong Li.
      N6-methyladenosine (m6A), one of the most prevalent RNA post-transcriptional modifications, is involved in numerous biological processes. In previous studies, the functions of m6A were typically identified by perturbing the activity of the methyltransferase complex. Here, we dissect the contribution of m6A to an individual-long noncoding RNA-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). The mutant MALAT1 lacking m6A-motifs significantly suppressed the metastatic potential of cancer cells both in vitro and in vivo in mouse. Super-resolution imaging showed that the concatenated m6A residues on MALAT1 acted as a scaffold for recruiting YTH-domain-containing protein 1 (YTHDC1) to nuclear speckles. We further reveal that the recognition of MALAT1-m6A by YTHDC1 played a critical role in maintaining the composition and genomic binding sites of nuclear speckles, which regulate the expression of several key oncogenes. Furthermore, artificially tethering YTHDC1 onto m6A-deficient MALAT1 largely rescues the metastatic potential of cancer cells.
    Keywords:  MALAT1 long noncoding RNA; RNA m(6)A modification; YTHDC1; metastasis; nuclear speckles
    DOI:  https://doi.org/10.1016/j.devcel.2021.01.015
  9. Cancer Control. 2021 Jan-Dec;28:28 1073274821997455
    Prognostic Roles of N6-Methyladenosine METTL3 in Different Cancers: A System Review and Meta-Analysis.
    KuangZheng Liu, Yue Gao, Kai Gan, YuQing Wu, Bin Xu, LiHua Zhang, Ming Chen.
       BACKGROUND: Recent studies have shown that methyltransferase-like 3, a catalytic enzyme that is predominant in the N6-methyladenosine methyltransferase system, is abnormally expressed in various types of carcinoma and is correlated with poorer prognosis. However, the clinical functions of methyltransferase-like 3 in the prognosis of tumors are not fully understood.
    METHODS: We identified studies by searching PubMed, Web of Science, and MedRvix for literature (up to June 30, 2020), and collected a total of 9 studies with 1257 patients for this meta-analysis. The cancer types included gastric cancer, breast cancer, non-small cell lung cancer, bladder cancer, colorectal cancer and ovarian. We further used The Cancer Genome Atlas dataset to validate the results.
    RESULTS: High methyltransferase-like 3 expression clearly predicted a worse outcome (high vs. low methyltransferase-like 3 expression group; hazard ratio = 2.09, 95% confidence interval 1.53-2.89, P = 0.0001). Moreover, methyltransferase-like 3 expression was associated with differentiation (moderate + poor vs. well, pooled odds ratio = 1.76, 95% confidence interval 1.32-2.35, P = 0.0001), and gender (male vs. female, pooled odds ratio = 0.73, 95% confidence interval 0.55-0.97, P = 0.029).
    CONCLUSION: Our results suggest that methyltransferase-like 3 upregulation is significantly associated with poor prognosis and could potentially function as a tumor biomarker in cancer prognosis.
    Keywords:  METTL3; TCGA; cancer; meta-analysis; overall survival; prognosis
    DOI:  https://doi.org/10.1177/1073274821997455
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