bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–06–05
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Identification of Two m6A Readers YTHDF1 and IGF2BP2 as Immune Biomarkers in Head and Neck Squamous Cell Carcinoma.
  2. METTL3 promotes cell cycle progression via m6A/YTHDF1-dependent regulation of CDC25B translation.
  3. DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m6A modification and translation for cytoprotective autophagy in cervical cancer.
  4. RNA m6A reader YTHDF1 facilitates inflammation via enhancing NLRP3 translation.
  5. The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers.
  6. Deguelin Attenuates Non-Small-Cell Lung Cancer Cell Metastasis by Upregulating PTEN/KLF4/EMT Signaling Pathway.
  7. Bioinformatics Analysis of the Characteristics and Correlation of m6A Methylation in Breast Cancer Progression.
  8. The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer.
  1. Front Genet. 2022 ;13 903634
    Identification of Two m6A Readers YTHDF1 and IGF2BP2 as Immune Biomarkers in Head and Neck Squamous Cell Carcinoma.
    Shaojie Li, Qiuji Wu, Jia Liu, Yahua Zhong.
      Background: N6-methyladenosine (m6A) is the most abundant internal modification pattern in mammals that a plays critical role in tumorigenesis and immune regulations. However, the effect of m6A modification on head and neck squamous cell carcinoma (HNSCC) has not been clearly studied. Methods: We screened m6A regulators that were significantly correlated with tumor immune status indicated by ImmuneScore using The Cancer Genome Atlas (TCGA) dataset and obtained distinct patient clusters based on the expression of these m6A regulators with the R package "CensusClusterPlus." We then performed gene set enrichment analysis (GSEA), CIBERSORT, and single-sample gene set enrichment analysis (ssGSEA) to assess the differences in gene function enrichment and tumor immune microenvironment (TIME) among these clusters. We further conducted differently expressed gene (DEG) analysis and weighted gene co-expression network analysis (WGCNA) and constructed a protein-protein interaction (PPI) network to determine hub genes among these clusters. Finally, we used the GSE65858 dataset as an external validation cohort to confirm the immune profiles related to the expression of m6A regulators. Results: Two m6A readers, YTHDF1 and IGF2BP2, were found to be significantly associated with distinct immune status in HNSCC. Accordingly, patients were divided into two clusters with Cluster 1 showing high expression of YTHDF1 and IGF2BP2 and Cluster 2 showing low expression levels of both genes. Clinicopathologically, patients from Cluster 1 had more advanced T stage and pathological grades than those from Cluster 2. GSEA showed that Cluster 1 was closely related to the RNA modification process and Cluster 2 was significantly correlated with immune regulations. Cluster 2 had a more active TIME characterized by a more relative abundance of CD8+ T cells and CD4+ T cells and higher levels of MHC I and MHC II molecules. We constructed a PPI network composed of 16 hub genes between the two clusters, which participated in the T-cell receptor signaling pathway. These results were externally validated in the GSE65858 dataset. Conclusions: The m6A readers, YTHDF1 and IGF2BP2, were potential immune biomarkers in HNSCC and could be potential treatment targets for cancer immunotherapy.
    Keywords:  HNSCC; IGF2BP2; YTHDF1; immune microenvironment; immunotherapy; m6A modification
    DOI:  https://doi.org/10.3389/fgene.2022.903634
  2. Int J Biol Sci. 2022 ;18(8): 3223-3236
    METTL3 promotes cell cycle progression via m6A/YTHDF1-dependent regulation of CDC25B translation.
    Huifeng Li, Ying Zhong, Guangxu Cao, Hezhan Shi, Yiyao Liu, Lingfeng Li, Peidi Yin, Jialing Chen, Zhendong Xiao, Bin Du.
      The cell cycle machinery controls cell proliferation and the dysregulation of the cell cycle lies at the heart of carcinogenesis. Thus, exploring the unknown regulators involved in the cell cycle not only contribute to better understanding of cell proliferation but also provide substantial improvement to cancer therapy. In this study, we identified that the expression of methyltransferase METTL3 was upregulated in the M phase. Overexpression of METTL3 facilitated cell cycle progression, induced cell proliferation in vitro and enhanced tumorigenicity in vivo, while knockdown of METTL3 reversed these processes. METTL3 induced CDC25B mRNA m6A modification in the M phase, which accelerated the translation of CDC25B mRNA through YTHDF1-dependent m6A modification. Clinical data analysis showed that METTL3 and CDC25B were highly expressed in cervical cancer. Our work reveals that a new mechanism regulates cell cycle progression through the METTL3/m6A/CDC25B pathway, which provides insight into the critical roles of m6A methylation in the cell cycle.
    Keywords:  METTL3; cell cycle; m6A
    DOI:  https://doi.org/10.7150/ijbs.70335
  3. RNA Biol. 2022 Jan;19(1): 751-763
    DARS-AS1 recruits METTL3/METTL14 to bind and enhance DARS mRNA m6A modification and translation for cytoprotective autophagy in cervical cancer.
    Weiwei Shen, Miaohua Zhu, Qiming Wang, Xiaoming Zhou, Jiaying Wang, Tingting Wang, Jing Zhang.
      Cervical cancer (CC) is one of the most prevalent malignancies among females. Cytoprotective autophagy could confer cancer cell tolerance to hypoxic stress, promoting cell survival and adaptation. Aspartyl-tRNA synthetase 1 antisense 1 (DARS-AS1) is an oncogenic long non-coding RNA (lncRNA) in various cancers, but how DARS-AS1 regulates cytoprotective autophagy in hypoxic environment in CC remains unclear. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were conducted to explore the interaction between hypoxia-inducible factor 1 subunit alpha (HIF1α) and DARS-AS1 promoter. Methylated RNA immunoprecipitation (MeRIP) followed by quantitative real-time polymerase-chain reaction (RT-qPCR) detected methylated RNA level. The process of autophagic maturation was monitored by immunofluorescence staining. Higher DARS-AS1 expression was found in CC tissues and cytoprotective. We also uncovered that hypoxic exposure induced cytoprotective autophagy via HIF1α/DARS-AS1/DARS axis. Moreover, DARS-AS1 was validated to facilitate DARS translation via recruiting N6-adenosine-methyltransferase methyltransferase like 3 (METTL3) and methyltransferase like 14 (METTL14), which bound with DARS mRNA DARS mRNA 5' untranslated region (5'UTR) and promoting its translation. The present study demonstrated that the 'HIF1α/DARS-AS1/DARS/ATG5/ATG3' pathway regulated the hypoxia-induced cytoprotective autophagy of CC and might be a promising target of therapeutic strategies for patients afflicted with CC.
    Keywords:  DARS-AS1; autophagy; cervical cancer; m6A modification
    DOI:  https://doi.org/10.1080/15476286.2022.2079889
  4. Biochem Biophys Res Commun. 2022 May 24. pii: S0006-291X(22)00787-2. [Epub ahead of print]616 76-81
    RNA m6A reader YTHDF1 facilitates inflammation via enhancing NLRP3 translation.
    Wei-Yuan Hao, Yan Lou, Guo-Ying Hu, Chao-Yi Qian, Wei-Ren Liang, Jun Zhao, Xiao-Hong Wang.
      N6-methyladenosine (m6A) modification of mRNAs is involved in multiple essential biological processes, dynamically regulated by m6A "writers", "erasers", and "readers". Yet, the detailed functional roles of RNA m6A reader proteins, such as YTHDFs, are largely unknown. Herein we show that YTHDF1 promotes pro-inflammatory IL-1β production in macrophages during bacterial infections. YTHDF1 overexpression promotes NLRP3 translation. In vivo knockdown of YTHDF1 facilitates survival in a mouse model of sepsis. Thus, YTHDF1 participates in inflammatory responses and subsequent injuries, serving as a new potential therapeutic target in clinical treatment of inflammatory diseases.
    Keywords:  Inflammation; N(6)-methyladenosine; NLRP3; YTHDF1
    DOI:  https://doi.org/10.1016/j.bbrc.2022.05.076
  5. Nat Commun. 2022 Jun 01. 13(1): 3061
    The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers.
    Yaodong Zhang, Zijian Ma, Changxian Li, Cheng Wang, Wangjie Jiang, Jiang Chang, Sheng Han, Zefa Lu, Zicheng Shao, Yirui Wang, Hongwei Wang, Chenyu Jiao, Dong Wang, Xiaofeng Wu, Hongbing Shen, Xuehao Wang, Zhibin Hu, Xiangcheng Li.
      Molecular variation between geographical populations and subtypes indicate potential genomic heterogeneity and novel genomic features within CCA. Here, we analyze exome-sequencing data of 87 perihilar cholangiocarcinoma (pCCA) and 261 intrahepatic cholangiocarcinoma (iCCA) cases from 3 Asian centers (including 43 pCCAs and 24 iCCAs from our center). iCCA tumours demonstrate a higher tumor mutation burden and copy number alteration burden (CNAB) than pCCA tumours, and high CNAB indicates a poorer pCCA prognosis. We identify 12 significantly mutated genes and 5 focal CNA regions, and demonstrate common mutations in post-transcriptional modification-related potential driver genes METTL14 and RBM10 in pCCA tumours. Finally we demonstrate the tumour-suppressive role of METTL14, a major RNA N6-adenosine methyltransferase (m6A), and illustrate that its loss-of-function mutation R298H may act through m6A modification on potential driver gene MACF1. Our results may be valuable for better understanding of how post-transcriptional modification can affect CCA development, and highlight both similarities and differences between pCCA and iCCA.
    DOI:  https://doi.org/10.1038/s41467-022-30708-7
  6. Dis Markers. 2022 ;2022 4090346
    Deguelin Attenuates Non-Small-Cell Lung Cancer Cell Metastasis by Upregulating PTEN/KLF4/EMT Signaling Pathway.
    Guohua Lu, Yinan Yao, Xiaochen Zhang, Dawei Cui, Jianying Zhou.
      Non-small-cell lung cancer (NSCLC) is the most common lung cancer and a major cause of cancer mortality worldwide. Deguelin plays a vital inhibitory role in NSCLC initiation and development. However, the downstream mechanism of deguelin-suppressed metastasis of NSCLC cells is still not completely understood. Interestingly, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and Krüppel-like factor 4 (KLF4) also contribute to inhibition of metastasis in NSCLC cells. Here, we demonstrated that deguelin significantly upregulated PTEN and KLF4 expressions and PTEN positively upregulated KLF4 expression in NSCLC cells including A549 and PC9 cells. Moreover, overexpressions of PTEN and KLF4 inhibited the migration and invasion of NSCLC cells, an effect similar to that of deguelin. Furthermore, overexpressions of PTEN and KLF4 could suppress the epithelial-mesenchymal transition (EMT), an effect also similar to that of deguelin. Additionally, deguelin displayed a significant antitumor ability by upregulating PTEN and KLF4 expressions in mice model with NSCLC cells. Together, these results indicated that deguelin could be a potential therapeutic agent through upregulating PTEN and KLF4 expressions for NSCLC therapy.
    DOI:  https://doi.org/10.1155/2022/4090346
  7. Contrast Media Mol Imaging. 2022 ;2022 4416439
    Bioinformatics Analysis of the Characteristics and Correlation of m6A Methylation in Breast Cancer Progression.
    Ping Zhao, Xinwei Huang, Anhao Wu, Xin Yang, Yang Fu, Yuhang Quan, Ji Zhang, Zhen Li, Qi Tang, Maohua Wang.
      Growing cutting-edge study has demonstrated the RNA m6A methylation's critical role in regulating tumorigenesis and progression all over the world, while it is still a mystery whether RNA m6A methylation has a positive impact on breast cancer treatment. In this article, we utilize bioinformatics to analyze three data sets including TCGA-BRCA, GSE96058, and GSE25066 and discover that breast cancer samples could be divided into 4 subtypes, which are quiescent, m6A methylation, protein-binding, and mixed, clarified by the expression level of m6A-related genes. R-survival analysis results also prove that the survival rate of breast cancer samples of the four subtypes significantly varies and remarkable differences in the number of exons' skip among the four subtypes can be seen according to the analysis of breast cancer gene expression characteristics. The degree of TP53 mutation and copy number loss is most obvious in the protein-binding subtype when it comes to tumor driver genes. Among the DNA damage repair genes, there is a sharp increase in the copy number of RAD54B of the protein-binding subtype, but fewer mutations in other DNA damage repair-related genes and copy number deletion is everywhere. Results of m6A methylation influencing on the proportion of infiltrated immune cells also indicate significant differences of the four m6A subgroups in macrophages M0 and mast cells resting which are closely correlated to patient prognosis. In addition, findings of the highest tumor stemness index and the lowest in the m6A methylated type in breast cancer samples can prove the critical role of the high expression of m6A reader protein in the progression of breast cancer.
    DOI:  https://doi.org/10.1155/2022/4416439
  8. Semin Cancer Biol. 2022 May 25. pii: S1044-579X(22)00120-1. [Epub ahead of print]
    The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer.
    Deepthi Ramesh-Kumar, Sonia Guil.
      RNA binding proteins that act at the post-transcriptional level display a richness of mechanisms to modulate the transcriptional output and respond to changing cellular conditions. The family of IGF2BP proteins recognize mRNAs modified by methylation and lengthen their lifecycle in the context of stable ribonucleoprotein particles to promote cancer progression. They are emerging as key 'reader' proteins in the epitranscriptomic field, driving the fate of bound substrates under physiological and disease conditions. Recent developments in the field include the recognition that noncoding substrates play crucial roles in mediating the pro-growth features of IGF2BP family, not only as regulated targets, but also as modulators of IGF2BP function themselves. In this review, we summarize the regulatory roles of IGF2BP proteins and link their molecular role as m6A modification readers to the cellular phenotype, thus providing a comprehensive insight into IGF2BP function.
    Keywords:  Cancer; Epitranscriptomics; IGF2BP proteins; M6A-RNA; Noncoding RNA
    DOI:  https://doi.org/10.1016/j.semcancer.2022.05.009
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