bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2021–07–18
eight papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Function and clinical significance of N6-methyladenosine in digestive system tumours.
  2. An m6A-Related Prognostic Biomarker Associated With the Hepatocellular Carcinoma Immune Microenvironment.
  3. Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Pterygium by MeRIP Sequencing.
  4. YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma.
  5. N6-methyladenosine Demethylase FTO Induces the Dysfunctions of Ovarian Granulosa Cells by Upregulating Flotillin 2.
  6. The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPARγ.
  7. A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication.
  8. ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
  1. Exp Hematol Oncol. 2021 Jul 10. 10(1): 40
    Function and clinical significance of N6-methyladenosine in digestive system tumours.
    Junchao Huang, Yingjie Shao, Wendong Gu.
      RNA modification, like DNA methylation, histone modification, non-coding RNA modification and chromatin rearrangement, plays an important role in tumours. N6-methyladenosine (m6A) is the most abundant RNA modification in cells, and it regulates RNA transcription, processing, splicing, degradation, and translation. m6A-associated proteins have been used as new biomarkers and therapeutic targets for tumour prediction and monitoring. There are three main types of proteins involved in m6A methylation: methyltransferases (METTL3, METTL14, WTAP, RBM15, ZC3H13 and KIAA1429), demethylases (FTO, ALKBH5 and ALKBH3) and RNA-binding proteins (YTHDF1-3, YTHDC1-2, IGF2BPs and HNRNPs). This article reviews the origins, characteristics and functions of m6A and its relationship with digestive system tumours based on recent research. The expression of m6A regulators can be used as an evaluation indicator of tumour growth and progression and as a prognostic indicator. In-depth research on m6A methylation in digestive system tumours may provide new directions for clinical prediction and further treatment.
    DOI:  https://doi.org/10.1186/s40164-021-00234-1
  2. Front Pharmacol. 2021 ;12 707930
    An m6A-Related Prognostic Biomarker Associated With the Hepatocellular Carcinoma Immune Microenvironment.
    Yingxi Du, Yarui Ma, Qing Zhu, Tongzheng Liu, Yuchen Jiao, Peng Yuan, Xiaobing Wang.
      Background: N6-methyladenosine (m6A) is related to the progression of multiple cancers. However, the underlying influences of m6A-associated genes on the tumor immune microenvironment in hepatocellular carcinoma (HCC) remain poorly understood. Therefore, we sought to construct a survival prediction model using m6A-associated genes to clarify the molecular and immune characteristics of HCC. Methods: HCC case data were downloaded from The Cancer Genome Atlas (TCGA). Then, by applying consensus clustering, we identified two distinct HCC clusters. Next, four m6A-related genes were identified to construct a prognostic model, which we validated with Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. Additionally, the molecular and immune characteristics in different subgroups were analyzed. Results: m6A RNA methylation regulators were differentially expressed between HCC and normal samples and linked with immune checkpoint expression. Using consensus clustering, we divided HCC samples into two subtypes with distinct clinical features. Cluster 2 was associated with unfavorable prognosis, higher immune checkpoint expression and immune cell infiltration levels. In addition, the immune and carcinogenic signaling pathways were enriched in cluster 2. Furthermore, we constructed a risk model using four m6A-associated genes. Patients with different risk scores had distinct survival times, expression levels of immunotherapy biomarkers, TP53 mutation rates, and sensitivities to chemotherapy and targeted therapy. Similarly, the model exhibited an identical impact on overall survival in the validation cohorts. Conclusion: The constructed m6A-based signature may be promising as a biomarker for prognostics and to distinguish immune characteristics in HCC.
    Keywords:  M6A; hepatocellular carcinoma; immune microenvironment; prognosis; therapy
    DOI:  https://doi.org/10.3389/fphar.2021.707930
  3. Front Cell Dev Biol. 2021 ;9 670528
    Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Pterygium by MeRIP Sequencing.
    Yaping Jiang, Xin Zhang, Xiaoyan Zhang, Kun Zhao, Jing Zhang, Chuanxi Yang, Yihui Chen.
       Aim: Pterygium is a common ocular surface disease, which is affected by a variety of factors. Invasion of the cornea can cause severe vision loss. N6-methyladenosine (m6A) is a common post-transcriptional modification of eukaryotic mRNA, which can regulate mRNA splicing, stability, nuclear transport, and translation. To our best knowledge, there is no current research on the mechanism of m6A in pterygium.
    Methods: We obtained 24 pterygium tissues and 24 conjunctival tissues from each of 24 pterygium patients recruited from Shanghai Yangpu Hospital, and the level of m6A modification was detected using an m6A RNA Methylation Quantification Kit. Expression and location of METTL3, a key m6A methyltransferase, were identified by immunostaining. Then we used m6A-modified RNA immunoprecipitation sequencing (MeRIP-seq), RNA sequencing (RNA-seq), and bioinformatics analyses to compare the differential expression of m6A methylation in pterygium and normal conjunctival tissue.
    Results: We identified 2,949 dysregulated m6A peaks in pterygium tissue, of which 2,145 were significantly upregulated and 804 were significantly downregulated. The altered m6A peak of genes were found to play a key role in the Hippo signaling pathway and endocytosis. Joint analyses of MeRIP-seq and RNA-seq data identified 72 hypermethylated m6A peaks and 15 hypomethylated m6A peaks in mRNA. After analyzing the differentially methylated m6A peaks and synchronously differentially expressed genes, we searched the Gene Expression Omnibus database and identified five genes related to the development of pterygium (DSP, MXRA5, ARHGAP35, TMEM43, and OLFML2A).
    Conclusion: Our research shows that m6A modification plays an important role in the development of pterygium and can be used as a potential new target for the treatment of pterygium in the future.
    Keywords:  GEO; Hippo signaling pathway; MeRIP sequencing; m6A; methyltransferase 3; pterygium
    DOI:  https://doi.org/10.3389/fcell.2021.670528
  4. J Hematol Oncol. 2021 Jul 10. 14(1): 109
    YTHDF2 facilitates UBXN1 mRNA decay by recognizing METTL3-mediated m6A modification to activate NF-κB and promote the malignant progression of glioma.
    Rui-Chao Chai, Yu-Zhou Chang, Xin Chang, Bo Pang, Song Yuan An, Ke-Nan Zhang, Yuan-Hao Chang, Tao Jiang, Yong-Zhi Wang.
       BACKGROUND: The prognosis for diffuse gliomas is very poor and the mechanism underlying their malignant progression remains unclear. Here, we aimed to elucidate the role and mechanism of the RNA N6,2'-O-dimethyladenosine (m6A) reader, YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), in regulating the malignant progression of gliomas.
    METHODS: YTHDF2 mRNA levels and functions were assessed using several independent datasets. Western blotting, quantitative polymerase chain reaction, and immunohistochemistry were used to evaluate the expression levels of YTHDF2 and other molecules in human and mouse tumor tissues and cells. Knockdown and overexpression were used to evaluate the effects of YTHDF2, methyltransferase-like 3 (METTL3), and UBX domain protein 1 (UBXN1) on glioma malignancy in cell and orthotopic xenograft models. RNA immunoprecipitation (RIP), methylated RIP, and RNA stability experiments were performed to study the mechanisms underlying the oncogenic role of YTHDF2.
    RESULTS: YTHDF2 expression was positively associated with a higher malignant grade and molecular subtype of glioma and poorer prognosis. YTHDF2 promoted the malignant progression of gliomas in both in vitro and in vivo models. Mechanistically, YTHDF2 accelerated UBXN1 mRNA degradation via METTL3-mediated m6A, which, in turn, promoted NF-κB activation. We further revealed that UBXN1 overexpression attenuated the oncogenic effect of YTHDF2 overexpression and was associated with better survival in patients with elevated YTHDF2 expression.
    CONCLUSIONS: Our findings confirmed that YTHDF2 promotes the malignant progression of gliomas and revealed important insight into the upstream regulatory mechanism of NF-κB activation via UBXN1 with a primary focus on m6A modification.
    Keywords:  Glioblastoma; METTL3; N6,2′-O-Dimethyladenosine; NF-κB activation; YTHDF2
    DOI:  https://doi.org/10.1186/s13045-021-01124-z
  5. Reprod Sci. 2021 Jul 12.
    N6-methyladenosine Demethylase FTO Induces the Dysfunctions of Ovarian Granulosa Cells by Upregulating Flotillin 2.
    Li Zhou, Xiao Han, Wei Li, Ning Wang, Lan Yao, Yunhe Zhao, Liqun Zhang.
      Polycystic ovarian syndrome (PCOS) is often accompanied by overweight/obesity and insulin resistance. The dysfunctions of ovarian granulosa cells (GCs) are closely linked with the pathogenesis of PCOS. Fat mass and obesity-associated gene (FTO), an N6-methyladenosine (m6A) demethylase, has been reported to be implicated in the risks and insulin resistance of PCOS. However, the roles of FTO in the development of GCs along with its m6A-related regulatory mechanisms are poorly defined. Cell proliferative ability was detected by MTT assay. Cell apoptotic rate was measured via flow cytometry. Insulin resistance was assessed by GLUT4 transport potential. The mRNA and protein levels of FTO and flotillin 2 (FLOT2) were determined by RT-qPCR and western blot assays, respectively. FLOT2 was screened out to be a potential FTO target through differential expression analysis for the GSE95728 dataset and target prediction analysis by POSTAR2 and STARBASE databases. The interaction between FTO and FLOT2 was analyzed by RNA immunoprecipitation (RIP) assay. The effect of FTO upregulation on FLOT2 m6A level was measured by methylated RIP (meRIP) assay. FLOT2 mRNA stability was examined by actinomycin D assay. FTO overexpression facilitated cell proliferation, hindered cell apoptosis, and induced insulin resistance in GCs. FTO promoted FLOT2 expression by reducing m6A level on FLOT2 mRNA and increasing FLOT2 mRNA stability. FLOT2 loss weakened the effects of FTO overexpression on cell proliferation/apoptosis and insulin resistance in GCs. FTO induced the dysfunctions of GCs by upregulating FLOT2, suggesting that FTO/FLOT2 might play a role in the pathophysiology of PCOS.
    Keywords:  FLOT2; FTO; N6-methyladenosine; Polycystic ovarian syndrome
    DOI:  https://doi.org/10.1007/s43032-021-00664-6
  6. Adv Sci (Weinh). 2021 07;8(13): 2100209
    The m6A Reader IGF2BP2 Regulates Macrophage Phenotypic Activation and Inflammatory Diseases by Stabilizing TSC1 and PPARγ.
    Xia Wang, Yuge Ji, Panpan Feng, Rucheng Liu, Guosheng Li, Junjie Zheng, Yaqiang Xue, Yaxun Wei, Chunyan Ji, Dawei Chen, Jingxin Li.
      Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin-like growth factor 2 messenger RNA (mRNA)-binding protein 2 (IGF2BP2)-deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2-/- macrophages are refractory to interleukin-4 (IL-4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6-methyladenosine (m6A)-dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)-high mobility group AT-hook 2-IGF2BP2-peroxisome proliferator activated receptor-γ axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.
    Keywords:  IGF2BP2; TSC1; inflammatory diseases; m6A reader; macrophage polarization
    DOI:  https://doi.org/10.1002/advs.202100209
  7. Blood. 2021 Jul 13. pii: blood.2021011707. [Epub ahead of print]
    A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex-Mediated DNA Replication.
    Yue Sheng, Jiangbo Wei, Fang Yu, Huanzhou Xu, Chunjie Yu, Qiong Wu, Yin Liu, Lei Li, Xiao-Long Cui, Xueying Gu, Bin Shen, Wei Li, Yong Huang, Sumita Bhaduri-Mcintosh, Chuan He, Zhijian Qian.
      YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in Acute Myeloid Leukemia (AML) and that it is required for proliferation and survival of human AML cells. Genetic deletion of Ythdc1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We find that Ythdc1 is also required for normal hematopoiesis and hematopoietic stem/progenitor cell (HSPC) maintenance in vivo. Notably, Ythdc1 haploinsufficiency reduces self-renewal of LSCs, but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides the compelling evidence to show an oncogenic role and a distinct mechanism of YTHDC1 in AML.
    DOI:  https://doi.org/10.1182/blood.2021011707
  8. Nat Cell Biol. 2021 Jul;23(7): 684-691
    ALKBH7-mediated demethylation regulates mitochondrial polycistronic RNA processing.
    Li-Sheng Zhang, Qing-Ping Xiong, Sonia Peña Perez, Chang Liu, Jiangbo Wei, Cassy Le, Linda Zhang, Bryan T Harada, Qing Dai, Xinran Feng, Ziyang Hao, Yuru Wang, Xueyang Dong, Lulu Hu, En-Duo Wang, Tao Pan, Arne Klungland, Ru-Juan Liu, Chuan He.
      Members of the mammalian AlkB family are known to mediate nucleic acid demethylation1,2. ALKBH7, a mammalian AlkB homologue, localizes in mitochondria and affects metabolism3, but its function and mechanism of action are unknown. Here we report an approach to site-specifically detect N1-methyladenosine (m1A), N3-methylcytidine (m3C), N1-methylguanosine (m1G) and N2,N2-dimethylguanosine (m22G) modifications simultaneously within all cellular RNAs, and discovered that human ALKBH7 demethylates m22G and m1A within mitochondrial Ile and Leu1 pre-tRNA regions, respectively, in nascent polycistronic mitochondrial RNA4-6. We further show that ALKBH7 regulates the processing and structural dynamics of polycistronic mitochondrial RNAs. Depletion of ALKBH7 leads to increased polycistronic mitochondrial RNA processing, reduced steady-state mitochondria-encoded tRNA levels and protein translation, and notably decreased mitochondrial activity. Thus, we identify ALKBH7 as an RNA demethylase that controls nascent mitochondrial RNA processing and mitochondrial activity.
    DOI:  https://doi.org/10.1038/s41556-021-00709-7
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