bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–05–01
fourteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation.
  2. Molecular mechanism of m6A methylation of circDLC1 mediated by RNA methyltransferase METTL3 in the malignant proliferation of glioma cells.
  3. The Emerging Role of N6-Methyladenosine RNA Methylation as Regulators in Cancer Therapy and Drug Resistance.
  4. Profiling m6A RNA Modifications in Low Amounts of Plant Cells Using Maize Meiocytes.
  5. Mechanism of METTL14 and m6A modification of lncRNA MALAT1 in the proliferation of oral squamous cell carcinoma cells.
  6. Dynamic N6-methyladenosine modification of lncRNA modulated by METTL3 during bacterial disease development in an echinoderm.
  7. Systematic expression analysis of m6A RNA methyltransferases in clear cell renal cell carcinoma.
  8. m6A Regulator-Mediated RNA Methylation Modification Patterns are Involved in the Pathogenesis and Immune Microenvironment of Depression.
  9. Identification of RNA Methylation-Related lncRNAs Signature for Predicting Hot and Cold Tumors and Prognosis in Colon Cancer.
  10. Structural and functional characterization of TrmM in m6 A modification of bacterial tRNA.
  11. Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.
  12. m6A RNA modifications: key regulators of normal and malignant hematopoiesis.
  13. Loss of METTL3 Attenuates Blastic Plasmacytoid Dendritic Cell Neoplasm Response to PRMT5 Inhibition via IFN Signalling.
  14. Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis.
  1. Cell Signal. 2022 Apr 21. pii: S0898-6568(22)00096-1. [Epub ahead of print]95 110335
    METTL3 mediates osteoblast apoptosis by regulating endoplasmic reticulum stress during LPS-induced inflammation.
    Yiping Kong, Yiwen Zhang, Yongjie Cai, Di Li, Baicheng Yi, Qiong Xu.
      Osteoblast apoptosis is a prominent factor for disrupting skeletal homeostasis in multiple inflammatory bone diseases. METTL3, a key methyltransferase that catalyzes the N6-methyladenosine (m6A) modification of mRNA, has recently been shown to exert a critical role in osteogenic differentiation. However, the function of METTL3 in osteoblast apoptosis under inflammatory conditions remains elusive. In the present study, we observed that the total m6A level and METTL3 expression were upregulated in differentiated osteoblasts and downregulated after LPS stimulation. METTL3 knockdown induced a higher apoptotic rate in LPS-treated osteoblasts. The expression of the antiapoptotic protein BCL-2 decreased, and the apoptotic proteins cleaved Caspase-3, cleaved PARP-1 and cleaved Caspase-12 increased following METTL3 knockdown. Meanwhile, METTL3 silencing inhibited osteoblast proliferation and decreased osteogenic marker expression, ALP activity and mineralized nodules. RNA-seq analysis revealed that differentially expressed genes were significantly enriched in unfolded protein response pathways in METTL3-deficient cells. METTL3 depletion upregulated the expression of the ER stress-related markers, including p-PERK, p-eIF2α, p-IRE1α, GRP78, ATF4, CHOP and ATF6. Inhibition of ER stress by 4-PBA remarkably rescued METTL3 knockdown-induced apoptosis and promoted osteoblast proliferation and differentiation. Mechanistically, METTL3 depletion enhanced the expression and mRNA stability of Grp78, and similar results were observed after YTHDF2 knockdown. RIP-qPCR revealed that YTHDF2 directly interacted with Grp78 mRNA and that the interaction relied on METTL3. Taken together, our study demonstrated that METTL3 knockdown enhanced Grp78 expression through YTHDF2-mediated RNA degradation, which elicited ER stress, thereby promoting osteoblast apoptosis and inhibiting cell proliferation and differentiation under LPS-induced inflammatory condition.
    Keywords:  ER stress; METTL3; N6-methyladenosine; apoptosis; mRNA stability; osteoblast differentiation
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110335
  2. Cell Death Discov. 2022 Apr 26. 8(1): 229
    Molecular mechanism of m6A methylation of circDLC1 mediated by RNA methyltransferase METTL3 in the malignant proliferation of glioma cells.
    Quansheng Wu, Xiaofeng Yin, Wenbo Zhao, Wenli Xu, Laizhao Chen.
      Glioma is an intracranial malignant tumor and remains largely incurable. Circular RNAs are prominent modulators in glioma progression. This study investigated the function of circular RNA DLC1 (circDLC1) in the malignant proliferation of glioma cells. circDLC1 expression in glioma tissues and cells was determined using RT-qPCR. The effect of circDLC1 on the malignant proliferation of glioma cells was analyzed using CCK-8, colony formation, and EdU staining assays. METTL3, miR-671-5p, and CTNNBIP1 expressions were determined. N6 methyladenosine (m6A) level of circDLC1 was analyzed using MeRIP. The binding relationship between miR-671-5p and circDLC1 or CTNNBIP1 was verified using RNA pull-down and dual-luciferase assays. A xenograft tumor model was established in nude mice to verify the effect of METTL3-mediated circDLC1 on glioma in vivo. circDLC1 was poorly expressed in glioma. circDLC1 overexpression suppressed glioma cell proliferation. Mechanically, METTL3-mediated m6A modification enhanced circDLC1 stability and upregulated circDLC1 expression in glioma. circDLC1 upregulated CTNNBIP1 transcription by competitively binding to miR-671-5p. METTL3 overexpression repressed the malignant proliferation of glioma via circDLC1/miR-671-5p/CTNNBIP1 in vivo. Collectively, METTL3-mediated m6A modification upregulated circDLC1 expression, and circDLC1 promoted CTNNBIP1 transcription by sponging miR-671-5p, thus repressing the malignant proliferation of glioma.
    DOI:  https://doi.org/10.1038/s41420-022-00979-6
  3. Front Pharmacol. 2022 ;13 873030
    The Emerging Role of N6-Methyladenosine RNA Methylation as Regulators in Cancer Therapy and Drug Resistance.
    Zhaolin Chen, Ying Hu, Le Jin, Fan Yang, Haiwen Ding, Lei Zhang, Lili Li, Tingting Pan.
      N6-methyladenosine (m6A) RNA methylation has been considered the most prevalent, abundant, and conserved internal transcriptional modification throughout the eukaryotic mRNAs. Typically, m6A RNA methylation is catalyzed by the RNA methyltransferases (writers), is removed by its demethylases (erasers), and interacts with m6A-binding proteins (readers). Accumulating evidence shows that abnormal changes in the m6A levels of these regulators are increasingly associated with human tumorigenesis and drug resistance. However, the molecular mechanisms underlying m6A RNA methylation in tumor occurrence and development have not been comprehensively clarified. We reviewed the recent findings on biological regulation of m6A RNA methylation and summarized its potential therapeutic strategies in various human cancers.
    Keywords:  N6-methyladenosine (m6A); RNA methylation; cancer; inflammation; therapeutic targets
    DOI:  https://doi.org/10.3389/fphar.2022.873030
  4. Methods Mol Biol. 2022 ;2484 313-331
    Profiling m6A RNA Modifications in Low Amounts of Plant Cells Using Maize Meiocytes.
    Drin Shabani, Thomas Dresselhaus, Stefanie Dukowic-Schulze.
      RNA modifications can influence gene expression via multiple aspects such as RNA stability and alternative splicing. The most prominent RNA modification is m6A (N6-methyladenosine). Its profiling from low starting amounts of <100 cells is challenging. We describe here a complete workflow from cell isolation to data analysis that is based on using an RNA CUT&RUN-supported m6A-RIP (RNA immunoprecipitation) procedure and a subsequent adaptor-tagging library synthesis. Male meiocytes isolated from maize anthers were used as a test system to establish the protocol.
    Keywords:  CUT&RUN; Maize; Meiocytes; RIP; RNA modification; m6A
    DOI:  https://doi.org/10.1007/978-1-0716-2253-7_21
  5. Oral Dis. 2022 Apr 25.
    Mechanism of METTL14 and m6A modification of lncRNA MALAT1 in the proliferation of oral squamous cell carcinoma cells.
    Jinli Li, Fatemeh Momen-Heravi, Xun Wu, Kaili He.
       OBJECTIVES: Methyltransferase-like 14 (METTL14) plays an epigenetic role in various cancer through N6-methyladenosine (m6A) modification. This study sought to analyze the mechanism of METTL14 in oral squamous cell carcinoma (OSCC) cell proliferation.
    METHODS: Expression levels of METTL14, lncRNA metastasis associated in lung adenocarcinoma transcript 1 (lncRNA MALAT1), microRNA (miR)-224-5p, and histone lysine demethylases 2A (KDM2A) in OSCC tissues (N=40) and cell lines (FaDu, SCC-25, CAL-27, and SCC-15) were detected. Cell viability and colony formation capacity were assessed. m6A level, stability, and subcellular localization of lncRNA MALAT1 were determined. Nude mouse xenograft tumor assay was performed to confirm the role of METTL14 in vivo.
    RESULTS: METTL14 and lncRNA MALAT1 were upregulated and miR-224-5p was downregulated in OSCC tissues and cells. Silencing METTL14 repressed OSCC cell viability and colony formation. Overexpression of MALAT1 and KDM2A or miR-224-5p downregulation reversed the inhibition of silencing METTL14 on OSCC cell proliferation. METTL14 induced m6A modification of MALAT1 to upregulate MALAT1. MALAT1 comparatively bound to miR-224-5p to promote KDM2A transcription. In vivo, METTL14 limited tumor growth via regulating MALAT1/miR-224-5p/ KDM2A.
    CONCLUSION: Overall, our findings verified the therapeutic role of silencing METTL14 in OSCC treatment through the MALAT1/miR-224-5p/KDM2A axis.
    Keywords:  LncRNA MALAT1; METTL14; Oral squamous cell carcinoma; m6A; miR-224-5p
    DOI:  https://doi.org/10.1111/odi.14220
  6. Fish Shellfish Immunol. 2022 Apr 25. pii: S1050-4648(22)00223-6. [Epub ahead of print]
    Dynamic N6-methyladenosine modification of lncRNA modulated by METTL3 during bacterial disease development in an echinoderm.
    Siyuan Zhang, Yina Shao, Dongdong Li, Chenghua Li.
      Long non-coding RNAs (lncRNAs) are novel functional non-coding RNAs which engaged in many aspects of biological processes. N6-methyladenosine (m6A) as a kind of abundant epitranscriptomic modification in eukaryotes, plays important roles in regulation of gene expression for various physiological functions. Our previous study demonstrated that sea cucumber lncRNAs were differentially expressed during bacterial infection. However, whether the post-transcriptional regulation of lncRNAs influenced by m6A modification in sea cucumbers with different stages of skin ulceration syndrome (SUS) are largely unknown. Here, we generated the genome-wide map of m6A lncRNAs in SUS-diseased and SUS-resistant sea cucumbers for the first time, revealed that m6A levels in lncRNAs were mainly upregulated in SUS-resistant group. Intriguingly, most of the m6A lncRNAs showed a positive correlation between the expression levels and m6A levels based on conjoint analysis, suggesting that m6A modification on a lncRNA may contribute to its RNA stability. Furthermore, the host genes of lncRNAs with dysregulated m6A peaks were enriched in immune pathway. More importantly, methyltransferase METTL3 was required for m6A methylation modification and played positive roles in lncRNA expression. Collectively, this study presents the comprehensive characters of m6A lncRNAs in marine invertebrate. These m6A modified lncRNAs may be served as potential regulators associated with SUS and provide a promising avenue for disease therapy through targeting METTL3.
    Keywords:  METTL3; Sea cucumber; Skin ulceration syndrome; lncRNA expression; m6A modification
    DOI:  https://doi.org/10.1016/j.fsi.2022.04.040
  7. BJUI Compass. 2021 Nov;2(6): 402-411
    Systematic expression analysis of m6A RNA methyltransferases in clear cell renal cell carcinoma.
    Larissa Gundert, Alexander Strick, Felix von Hagen, Doris Schmidt, Niklas Klümper, Yuri Tolkach, Marieta Toma, Glen Kristiansen, Manuel Ritter, Jörg Ellinger.
       Objectives: To investigate the regulation of the N-6-methyladenosine (m6A) methyltransferases METTL3, METTL14, WTAP, KIAA1429, and METTL4, referred to as "m6A writers," in clear cell renal cell carcinoma (ccRCC), and other RCC subtypes in respect of the potential prognostic value.
    Patients and methods: Tissue samples were collected within the framework of the Biobank at the Center for Integrated Oncology Bonn. The expression of the methyltransferases was systematically determined in clear cell renal carcinoma (ccRCC) on the RNA (real-time PCR) and protein level (immunohistochemistry). Additionally, protein expression of the m6A writers was further investigated in papillary RCC, chromophobe RCC, sarcomatoid RCC, oncocytoma, and normal renal tissue (immunohistochemistry).
    Results: The expression of all m6A-methyltransferases was significantly downregulated in ccRCC compared to benign renal tissue. Low m6A-methyltransferase levels were correlated with higher histological grade, advanced pT-stage, pN-stage, and metastatic disease. Reduced m6A-methyltransferase expression was associated with shorter overall survival.
    Conclusion: In conclusion, m6A-methyltransferases are dysregulated in ccRCC and might act as tumor suppressor genes, which could be of particular importance for future diagnostic and therapeutic options.
    Keywords:  KIAA1429; METTL14; METTL3; METTL4; WTAP; ccRCC; m6A; methyltransferases
    DOI:  https://doi.org/10.1002/bco2.89
  8. Front Genet. 2022 ;13 865695
    m6A Regulator-Mediated RNA Methylation Modification Patterns are Involved in the Pathogenesis and Immune Microenvironment of Depression.
    Ye Wang, Xinyi Wang, Chenyi Yang, Wei Hua, Haiyun Wang.
      Depression is a genetical disease characterized by neuroinflammatory symptoms and is difficult to diagnose and treat effectively. Recently, modification of N6-methyladenosine (m6A) at the gene level was shown to be closely related to immune regulation. This study was conducted to explore the effect of m6A modifications on the occurrence of depression and composition of the immune microenvironment. We downloaded gene expression profile data of healthy and depressed rats from the Gene Expression Omnibus. We described the overall expression of m6A regulators in animal models of depression and constructed risk and clinical prediction models using training and validation sets. Bioinformatics analysis was performed using gene ontology functions, gene set enrichment analysis, gene set variation analysis, weighted gene co-expression network analysis, and protein-protein interaction networks. We used CIBERSORT to identify immune-infiltrating cells in depression and perform correlation analysis. We then constructed two molecular subtypes of depression and assessed the correlation between the key genes and molecular subtypes. Through differential gene analysis of m6A regulators in depressed rats, we identified seven m6A regulators that were significantly upregulated in depressed rats and successfully constructed a clinical prediction model. Gene Ontology functional annotation showed that the m6A regulators enriched differentially expressed genes in biological processes, such as the regulation of mRNA metabolic processes. Further, 12 hub genes were selected from the protein-protein interaction network. Immune cell infiltration analysis showed that levels of inflammatory cells, such as CD4 T cells, were significantly increased in depressed rats and were significantly correlated with the depression hub genes. Depression was divided into two subtypes, and the correlation between hub genes and these two subtypes was clarified. We described the effect of m6A modification on the pathogenesis of depression, focusing on the role of inflammatory infiltration.
    Keywords:  N6-methyladenosine; biomarker; depression; epigenetics; immune microenvironment
    DOI:  https://doi.org/10.3389/fgene.2022.865695
  9. Front Genet. 2022 ;13 870945
    Identification of RNA Methylation-Related lncRNAs Signature for Predicting Hot and Cold Tumors and Prognosis in Colon Cancer.
    Rong He, Changfeng Man, Jiabin Huang, Lian He, Xiaoyan Wang, Yakun Lang, Yu Fan.
      N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), and 7-methylguanosine (m7G) are the major forms of RNA methylation modifications, which are closely associated with the development of many tumors. However, the prognostic value of RNA methylation-related long non-coding RNAs (lncRNAs) in colon cancer (CC) has not been defined. This study summarised 50 m6A/m1A/m5C/m7G-related genes and downloaded 41 normal and 471 CC tumor samples with RNA-seq data and clinicopathological information from The Cancer Genome Atlas (TCGA) database. A total of 1057 RNA methylation-related lncRNAs (RMlncRNAs) were identified with Pearson correlation analysis. Twenty-three RMlncRNAs with prognostic values were screened using univariate Cox regression analysis. By consensus clustering analysis, CC patients were classified into two molecular subtypes (Cluster 1 and Cluster 2) with different clinical outcomes and immune microenvironmental infiltration characteristics. Cluster 2 was considered to be the "hot tumor" with a better prognosis, while cluster 1 was regarded as the "cold tumor" with a poorer prognosis. Subsequently, we constructed a seven-lncRNA prognostic signature using the least absolute shrinkage and selection operator (LASSO) Cox regression. In combination with other clinical traits, we found that the RNA methylation-related lncRNA prognostic signature (called the "RMlnc-score") was an independent prognostic factor for patients with colon cancer. In addition, immune infiltration, immunotherapy response analysis, and half-maximum inhibitory concentration (IC50) showed that the low RMlnc-score group was more sensitive to immunotherapy, while the high RMlnc-score group was sensitive to more chemotherapeutic agents. In summary, the RMlnc-score we developed could be used to predict the prognosis, immunotherapy response, and drug sensitivity of CC patients, guiding more accurate, and personalized treatment regimens.
    Keywords:  RNA methylation; colon cancer; immunotherapy; long non-coding RNA; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fgene.2022.870945
  10. Protein Sci. 2022 May;31(5): e4319
    Structural and functional characterization of TrmM in m6 A modification of bacterial tRNA.
    Hyeonju Jeong, Yeji Lee, Jungwook Kim.
      N6 -methyladenosine (m6 A), widely distributed in both coding and noncoding RNAs, regulates the epigenetic signals and RNA metabolism in eukaryotes. Although this posttranscriptional modification is frequently observed in messenger and ribosomal RNA, it is relatively rare in transfer RNA. In Escherichia coli, TrmM encoded by yfiC is the tRNA-specific N6 methyltransferase, which modifies the A37 residue of tRNAVal (cmo5 UAC) using S-adenosyl-l-methionine as a methyl donor. However, the structure-function relationship of this enzyme is not completely understood. In this report, we determined two x-ray crystal structures of Mycoplasma capricolum TrmM with and without S-adenosyl-l-homocysteine, which is a reaction product. We also demonstrated the cellular and in vitro activities of this enzyme in the m6 A modification of tRNA and the requirement of a divalent metal ion for its function, which is unprecedented in other RNA N6 methyltransferases, including the E. coli TrmM. Our results reveal that the dimeric form of M. capricolum TrmM is important for efficient tRNA binding and catalysis, thereby offering insights into the distinct substrate specificity of the monomeric E. coli homolog.
    Keywords:  m6A; methyltransferase; protein crystal; tRNA modification; x-ray structure
    DOI:  https://doi.org/10.1002/pro.4319
  11. Gerontology. 2022 Apr 25. 1-15
    Senolytics Cocktail Dasatinib and Quercetin Alleviate Human Umbilical Vein Endothelial Cell Senescence via the TRAF6-MAPK-NF-κB Axis in a YTHDF2-Dependent Manner.
    Ting Fan, Yi Du, Mingwan Zhang, Austin Rui Zhu, Jianjun Zhang.
       INTRODUCTION: Senescent cells play a key role in the initiation and development of various age-related diseases. Human umbilical vein endothelial cells (HUVECs) senescence is closely associated with age-related cardiovascular diseases. Accumulating evidence has demonstrated that senolytics, the combination of dasatinib and quercetin (D+Q), could selectively eliminate senescent cells. N6-methyladenosine (m6A), the most abundant internal transcript modification, greatly influences RNA metabolism and modulates gene expression. We aimed to investigate whether RNA m6A functions in lipopolysaccharide (LPS)-induced HUVECs senescence and D+Q suppress HUVECs senescence by regulating RNA m6A.
    METHODS: Senescence-associated β-galactosidase activity, western blot, and real-time quantitative polymerase chain reaction were performed to demonstrate that D+Q suppress HUVECs senescence. Methylated RNA immunoprecipitation (MeRIP)-qPCR assay and RIP-qPCR confirmed that RNA m6A plays a key role in the suppression of HUVECs senescence by D+Q. Chromatin immunoprecipitation and mRNA stability assay were carried out to prove that D+Q alleviate HUVECs senescence in a YTHDF2-dependent manner.
    RESULTS: Here, we demonstrate that D+Q alleviate LPS-induced senescence in HUVECs via inhibiting autocrine and paracrine of the senescence-associated secretory phenotype (SASP). We further confirm that D+Q alleviate HUVECs senescence via the TNF receptor-associated factor 6 (TRAF6)-MAPK pathway. Mechanically, this study validates that D+Q suppress SASP by upregulating m6A reader YTHDF2. Besides, YTHDF2 regulates the stability of MAP2K4 and MAP4K4 mRNAs.
    CONCLUSION: Collectively, we first identified that D+Q alleviate LPS-induced senescence in HUVECs via the TRAF6-MAPK-NF-κB axis in a YTHDF2-dependent manner, providing novel ideas for clinical treatment of age-related cardiovascular diseases.
    Keywords:  Dasatinib; Inflammation; Quercetin; Senescence; Senolytics; YTHDF2
    DOI:  https://doi.org/10.1159/000522656
  12. Exp Hematol. 2022 Apr 26. pii: S0301-472X(22)00204-1. [Epub ahead of print]
    m6A RNA modifications: key regulators of normal and malignant hematopoiesis.
    Pia Sommerkamp, Jessie A Brown, Myriam L R Haltalli, François E Mercier, Ly P Vu, Kamil R Kranc.
      Post-transcriptional RNA modifications determine RNA fate by influencing numerous processes such as translation, decay and localization. One of the most abundant RNA modifications is N6-methyladenoside (m6A), which has been shown to be important in healthy as well as malignant hematopoiesis. Several proteins representing key players in m6A RNA biology, such as m6A writers, erasers and readers, were recently reported to be essential for hematopoietic stem cell (HSC) function. In leukemia, expression of m6A regulators has been shown to be increased, opening up potential opportunities for therapeutic exploitation by targeting them in blood malignancies. These recent discoveries were the focus of the Fall 2021 International Society for Experimental Hematology New Investigator webinar. We review here the latest findings in the field of mRNA modifications in normal and malignant hematopoiesis and how this might open up novel therapeutic options.
    Keywords:  hematopoiesis; hematopoietic stem cell; leukemia; m(6)A; m(6)A regulators
    DOI:  https://doi.org/10.1016/j.exphem.2022.04.006
  13. Blood Adv. 2022 Apr 28. pii: bloodadvances.2021006306. [Epub ahead of print]
    Loss of METTL3 Attenuates Blastic Plasmacytoid Dendritic Cell Neoplasm Response to PRMT5 Inhibition via IFN Signalling.
    Malini Rethnam, Darren Qiancheng Tan, Shi Hao Tan, Jia Li, Rui Yokomori, Ying Li, Henry Yang, Takaomi Sanda, Toshio Suda.
      Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with poor clinical outcomes. Dysregulated MYC expression, which is associated with protein arginine methyltransferase 5 (PRMT5) dependency, is a recurrent feature of BPDCN. Although recent studies have reported a PRMT5 gene signature in BPDCN patient samples, the role of PRMT5 in BPDCN remains unexplored. Here, we demonstrate that BPDCN is highly sensitive to PRMT5 inhibition. Consistent with the upregulation of PRMT5 in BPDCN, we show that pharmacological inhibition (GSK3326595) of PRMT5 inhibits growth of the patient-derived BPDCN cell line CAL-1, in vitro and mitigated tumour progression in our mouse xenograft model. Interestingly, RNA-sequencing analysis revealed that PRMT5 inhibition increases intron retention in several key RNA methylation genes, including METTL3, which was accompanied by a dose-dependent decrease in METTL3 expression. Notably, METTL3's function of cellular m6A RNA modification was also affected by PRMT5 inhibition in CAL-1 cells. Intriguingly, METTL3 depletion in CAL-1 caused a significant increase in interferon signalling which was further elevated upon PRMT5 inhibition. Importantly, we discovered that this increase in interferon signalling attenuated the sensitivity of METTL3-depleted CAL-1 cells to PRMT5 inhibition. Correspondingly, stimulation of interferon signalling via TLR7 agonists weakened CAL-1 cells' sensitivity to PRMT5 inhibition. Overall, our findings implicate PRMT5 as a therapeutic target in BPDCN and provide insight into the involvement of METTL3 and interferon pathway in regulating response to PRMT5 inhibition.
    DOI:  https://doi.org/10.1182/bloodadvances.2021006306
  14. Drug Deliv. 2022 Dec;29(1): 1257-1271
    Exosome-transmitted circVMP1 facilitates the progression and cisplatin resistance of non-small cell lung cancer by targeting miR-524-5p-METTL3/SOX2 axis.
    Hongya Xie, Jie Yao, Yuxuan Wang, Bin Ni.
       BACKGROUND: Circular RNAs (circRNAs) play important regulatory roles in multiple human malignancies, including non-small cell lung cancer (NSCLC). Here, we explored the role of circRNA vacuole membrane protein 1 (circVMP1) in NSCLC progression and cisplatin (DDP) resistance.
    METHODS: The DDP resistance, proliferation, sphere formation ability, migration, invasion, and apoptosis of NSCLC cells were analyzed by Cell Counting Kit-8 (CCK8) assay, 5-ethynyl-2'-deoxyuridine (EdU) assay, sphere formation assay, wound healing assay, Transwell assay, and flow cytometry. Methylated RIP-qPCR (MeRIP-qPCR) was conducted to analyze the m6A modification level of SRY-box transcription factor 2 (SOX2). Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were performed to confirm the intermolecular interaction. Exosomes were identified by transmission electron microscopy (TEM) and characterized by nanoparticle tracking analysis (NTA).
    RESULTS: CircVMP1 expression was markedly elevated in DDP-resistant NSCLC cell lines compared with their parental cell lines. CircVMP1 absence restrained the proliferation, sphere formation, migration, invasion, and DDP resistance and promoted the apoptosis of DDP-resistant NSCLC cells. CircVMP1 acted as microRNA-524-5p (miR-524-5p) sponge to up-regulate the expression of methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3) and SOX2. CircVMP1 silencing restrained the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells by targeting miR-524-5p. Exosomal circVMP1 disseminated the malignant properties and DDP resistance to DDP-sensitive cells. Exosomal circVMP1 elevated the DDP resistance of xenograft tumors in vivo. Exosomal circVMP1 was up-regulated in the serum samples of DDP-resistant NSCLC patients compared with DDP-sensitive patients.
    CONCLUSION: Exosome-mediated transmission of circVMP1 promoted NSCLC progression and DDP resistance by targeting miR-524-5p-METTL3/SOX2 axis.HighlightsCircVMP1 level is up-regulated in DDP-resistant NSCLC cell lines compared with DDP-sensitive cell lines.CircVMP1 absence restrains the malignant behaviors and DDP resistance of A549/DDP and H1299/DDP cells.CircVMP1-miR-524-5p/METTL3/SOX2 axis is identified for the first time.CircVMP1 plays an oncogenic role by targeting miR-524-5p-METTL3/SOX2 axis in A549/DDP and H1299/DDP cells.Exosomal circVMP1 transmits the malignant properties and DDP resistance to DDP-sensitive cells.
    Keywords:  METTL3; SOX2; circVMP1; cisplatin; exosome; miR-524-5p
    DOI:  https://doi.org/10.1080/10717544.2022.2057617
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