bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2023‒10‒15
thirteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms.
  2. m6A Writer METTL3-Mediated lncRNA LINC01125 Prevents the Malignancy of Papillary Thyroid Cancer.
  3. METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3.
  4. METTL3-Mediated RNA m6A Modification Regulates the Angiogenic Behaviors of Retinal Endothelial Cells by Methylating MMP2 and TIE2.
  5. KIAA1429 Promotes Nasopharyngeal Carcinoma Progression by Mediating m6A Modification of PTGS2.
  6. METTL3-mediated m6A modification of lncRNA SNHG3 accelerates gastric cancer progression by modulating miR-186-5p/cyclinD2 axis.
  7. CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes.
  8. IGF2BP2 acts as a m6A modification regulator in laryngeal squamous cell carcinoma through facilitating CDK6 mRNA stabilization.
  9. Crosstalk Between m6A RNA Methylation and miRNA Biogenesis in Cancer: An Unholy Nexus.
  10. The m6A reader YTHDC1-mediated lncRNA CTBP1-AS2 m6A modification accelerates cholangiocarcinoma progression.
  11. Comprehensive Investigation of m6A Regulators for Prognosis in Head and Neck Squamous Cell Carcinoma.
  12. Dynamic alterations of the transcriptome-wide m6A methylome in cytogenetically normal acute myeloid leukaemia during initial diagnosis and relapse.
  13. N6-Methyladenosine (m6A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1.
  1. Front Pharmacol. 2023 ;14 1260300
    Overexpression of FTO inhibits excessive proliferation and promotes the apoptosis of human glomerular mesangial cells by alleviating FOXO6 m6A modification via YTHDF3-dependent mechanisms.
    Xingxing Zhuang, Tao Liu, Liangbing Wei, Jiarong Gao.
      Background: N6-methyladenosine (m6A) is a prevalent post-transcriptional modification presented in messenger RNA (mRNA) of eukaryotic organisms. Chronic glomerulonephritis (CGN) is characterised by excessive proliferation and insufficient apoptosis of human glomerular mesangial cells (HGMCs) but its underlying pathogenesis remains undefined. Moreover, the role of m6A in CGN is poorly understood. Methods: The total level of m6A modification was detected using the m6A quantification assay (Colorimetric). Cell proliferation was assessed by EdU cell proliferation assay, and cell apoptosis was detected by flow cytometry. RNA sequencing was performed to screen the downstream target of fat mass and obesity-associated protein (FTO). MeRIP-qPCR was conducted to detect the m6A level of forkhead box o6 (FOXO6) in HGMCs. RIP assay was utilized to indicate the targeting relationship between YTH domain family 3 (YTHDF3) and FOXO6. Actinomycin D assay was used to investigate the stability of FOXO6 in HGMCs. Results: The study found that the expression of FTO was significantly reduced in lipopolysaccharide (LPS)-induced HGMCs and renal biopsy samples of patients with CGN. Moreover, FTO overexpression and knockdown could regulate the proliferation and apoptosis of HGMCs. Furthermore, RNA sequencing and cellular experiments revealed FOXO6 as a downstream target of FTO in regulating the proliferation and apoptosis of HGMCs. Mechanistically, FTO overexpression decreases the level of FOXO6 m6A modification and reduces the stability of FOXO6 mRNA in a YTHDF3-dependent manner. Additionally, the decreased expression of FOXO6 inhibits the PI3K/AKT signaling pathway, thereby inhibiting the proliferation and promoting apoptosis of HGMCs. Conclusion: This study offers insights into the mechanism through which FTO regulates the proliferation and apoptosis of HGMCs by mediating m6A modification of FOXO6 mRNA. These findings also suggest FTO as a potential diagnostic marker and therapeutic target for CGN.
    Keywords:  FOXO6; FTO; cell apoptosis; cell proliferation; glomerular mesangial cells; m6A modification
    DOI:  https://doi.org/10.3389/fphar.2023.1260300
  2. Crit Rev Immunol. 2023 ;43(3): 43-53
    m6A Writer METTL3-Mediated lncRNA LINC01125 Prevents the Malignancy of Papillary Thyroid Cancer.
    Tianyou He, Hailiang Xia, Baojie Chen, Ziqi Duan, Chaogang Huang.
      BACKGROUND: Long non-coding RNA (lncRNA) LINC01125 is an anti-tumor factor in a variety of tumors, and regulates cancer cell function. However, its function and mechanism of N6-methyladenosine (m6A) modification in papillary thyroid cancer (PTC) tumorigenesis remain unclear.AIMS: This study aimed to reveal the function and m6A modification of LINC01125 in PTC tumorigenesis.
    METHODS: The LINC01125 and methyltransferase-like 3 (METTL3) levels in PTC cells and tissues was assessed by qRT-PCR. The binding relationship among LINC01125 and METTL3 was determined by MeRIP, Pearson, bioinformatics, and RNA stabilization analysis. Transwell assays were performed to confirm the changes of PTC cell migration and invasion. Cell proliferation was revealed by CCK-8 as well as colony formation assays.
    RESULTS: Low expression of LINC01125 and METTL3 was identified in PTC. LINC01125 was a downstream target of METTL3-mediated m6A modification and was stably upregulated via METTL3. Cell invasion, migration, viability, and colony formation levels were decreased when LINC01125 or METTL3 was upregulated. Inhibition of LINC01125 had the opposite impact, promoting cell proliferation and metastasis, and reversing METTL3 overexpression-resulted cell malignancy suppression.
    CONCLUSIONS: Overall, this study proved that the m6A modification of LINC01125 was mediated by METTL3 and LINC01125 inhibited cell invasion, migration and proliferation, thereby suppressing the development of PTC. This points to the LINC01125-m6A-METTL3 axis as a possible prospective target for future treatment of PTC.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2023050267
  3. Sci Rep. 2023 Oct 12. 13(1): 17292
    METTL3/IGF2BP2 axis affects the progression of colorectal cancer by regulating m6A modification of STAG3.
    Jianmei Yi, Feng Peng, Jingli Zhao, Xiaosong Gong.
      Colorectal cancer (CRC) is among the commonest malignant tumors of humans. Existing evidence has linked the poor prognosis of CRC with high expression of stromal antigen 3 (STAG3), but, the exact biological effect of STAG3 in CRC is still unclear. The aim of this research is to reveal the biological function and molecular mechanism of STAG3 in CRC. To investigate the differential expression of STAG3 in CRC tissues and cell lines compared to normal colon tissues and cell lines, Western blot (WB) and quantitative real-time PCR (qRT-PCR) techniques were utilized. STAG3 N6-methyladenosine (m6A) modification level were identified using m6A RNA immunoprecipitation (MeRIP). Additionally, the functional roles of methyltransferase-like protein 3 (METTL3) and insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) in CRC were explored by manipulating their levels via knockdown or overexpression. Cell proliferation was evaluated through Cell Counting Kit 8 (CCK-8) and clone formation experiments, while cell migration was assessed through wound healing experiments. Furthermore, cell apoptosis was detected using flow cytometry, and the protein expressions associated with proliferation and apoptosis were detected using WB. To identify the specific binding of target genes, RIP and pull-down assays were employed. Finally, the biological function of STAG3 in vivo was investigated through a xenotransplantation mouse tumor model. In CRC tissues and cell lines, STAG3 was up-regulated and accompanied by m6A methylation. Additionally, the expression of METTL3 was found to be upregulated in CRC tissues. Knocking down METTL3 resulted in a decrease in both the m6A level and protein expression of STAG3, inhibited cell proliferation and migration while promoting apoptosis, which were restored through STAG3 overexpression. Furthermore, online prediction indicated the interaction between STAG3 mRNA and IGF2BP2 protein, which was further verified by RIP experiments. IGF2BP2 downregulation led to decreased STAG3 protein expression, cell proliferation, and migration, but increased apoptosis. However, these impacts were reversed by STAG3 overexpression. Finally, subcutaneous tumor experiments conducted in nude mice also confirmed that METTL3 regulated CRC progression through STAG3 in vivo. The METTL3/IGF2BP2/STAG3 axis affects CRC progression in an m6A modification-dependent manner. This may guide targeted therapy in CRC patients.
    DOI:  https://doi.org/10.1038/s41598-023-44379-x
  4. Invest Ophthalmol Vis Sci. 2023 Oct 03. 64(13): 18
    METTL3-Mediated RNA m6A Modification Regulates the Angiogenic Behaviors of Retinal Endothelial Cells by Methylating MMP2 and TIE2.
    Yong Lin, Guangying Luo, Qi Liu, Rusen Yang, Peter Sol Reinach, Dongsheng Yan.
      Purpose: N6-methyladenosine (m6A) is a commonly occurring modification of mRNAs, catalyzed by a complex containing methyltransferase like 3 (METTL3). Our research aims to explore how METTL3-dependent m6A modification affects the functions of retinal endothelial cells (RECs).Methods: An oxygen-induced retinopathy (OIR) mouse model was established, and RECs were isolated using magnetic beads method. Human retinal microvascular endothelial cells (HRMECs) were treated with normoxia (21% O2) or hypoxia (1% O2). Dot blot assay determined m6A modification levels. Quantitative RT-PCR and Western blot detected the mRNA and protein expression levels of the target candidates, respectively. Genes were knocked down by small interfering RNA transfection. Matrigel-based angiogenesis and transwell assays evaluated the abilities of endothelial tube formation and migration, respectively. Methylated RNA immunoprecipitation-qPCR determined the levels of m6A modification in the target genes.
    Results: The m6A modification levels were significantly upregulated in the retinas and RECs of OIR mice. Exposure to hypoxia significantly elevated both METTL3 expression and m6A modification levels in HRMECs. METTL3 knockdown curtailed endothelial tube formation and migration in vitro under both normoxic and hypoxic conditions. Concurrently, this knockdown in HRMECs resulted in reduced m6A modification levels of MMP2 and TIE2 transcripts, subsequently leading to a decrease in their respective protein expressions. Notably, knockdown of MMP2 and TIE2 also markedly inhibited the angiogenic activities of HRMECs.
    Conclusions: METTL3-mediated m6A modification promotes the angiogenic behaviors of RECs by targeting MMP2 and TIE2, suggesting its significance in retinal angiogenesis and METTL3 as a potential therapeutic target.
    DOI:  https://doi.org/10.1167/iovs.64.13.18
  5. Crit Rev Immunol. 2023 ;43(4): 15-27
    KIAA1429 Promotes Nasopharyngeal Carcinoma Progression by Mediating m6A Modification of PTGS2.
    Lingling Wu, Yuanhong Zhou, Jun Fu.
      Emerging evidence suggests that dysregulation of a N6-methyladenosine (m6A) methyltransferase KIAA1429 participates in the pathogenesis of multiple cancers except for nasopharyngeal carcinoma (NPC). This study is aimed to explore the function of KIAA1429 in NPC progression. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets were used to confirm the mRNA expression in NPC by bioinformatic analysis. The levels of KIAA1429 and PTGS2 was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. To investigate the effects of KIAA1429/PTGS2 knockdown or overexpression vectors on NPC cell malignancy, cell and animal experiments were performed. Finally, MeRIP and mRNA stability assays were used to verify the m6A modification and mRNA stability, respectively. KIAA1429 was upregulated in NPC tissues and cells. After transfecting KIAA1429 knockdown or overexpression vectors in NPC cells, we proved that KIAA1429 overexpression promoted proliferation, migration, invasion, and tumor growth, whereas KIAA1429 knockdown showed the opposite effect. Our results also indicated that KIAA1429 mediated m6A modification of PTGS2, enhancing PTGS2 mRNA stability in NPC cells. In addition, PTGS2 could also regulate the effects of KIAA1429 on NPC cell malignancy. This study confirmed the oncogenic function of KIAA1429 in NPC through m6A-modification of PTGS2, suggesting that targeting KIAA1429-mediated m6A modification of PTGS2 might provide a new therapeutic strategy for NPC.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2023050249
  6. Int J Immunopathol Pharmacol. 2023 Jan-Dec;37:37 3946320231204694
    METTL3-mediated m6A modification of lncRNA SNHG3 accelerates gastric cancer progression by modulating miR-186-5p/cyclinD2 axis.
    Guo Ji, Xiu Wang, Hao Xi.
      OBJECTIVES: METTL3 as an m6A methyltransferase acts in diverse malignancies including gastric cancer (GC). We aimed to reveal the underlying mechanisms by which METTL3 contributes to gastric carcinogenesis.METHODS: The association of METTL3 and SNHG3 with GC was analyzed by qRT-PCR, Western blot, and TCGA cohort. The functional experiments were implemented to uncover the role of METTL3 in GC. m6A dot blot and MeRIP were used to determine METTL3-mediated m6A modification of lncRNA SNHG3. The effect of METTL3 on SNHG3-mediated miR-186-5p/cyclinD2 axis was evaluated by luciferase gene report, RT-qPCR, and Western blot assays.
    RESULTS: We found that METTL3 was remarkably elevated in GC tissues and correlated with poor survival in patients with GC. Silencing of METTL3 impaired GC cell growth and invasion, whereas restored METTL3 expression promoted these effects. Mechanistically, reduced expression of METTL3 decreased SNHG3 m6A level and caused a decrease in SNHG3 expression, which could further act as a sponge of miR-186-5p to upregulate cyclinD2. Overexpression of SNHG3 attenuated METTL3 knockdown-induced anti-proliferating and miR-186-5p upregulation and cyclinD2 downregulation.
    CONCLUSION: We find that METTL3-mediated m6A modification of lncRNA SNHG3 accelerates GC progression by modulating miR-186-5p/cyclinD2 axis.
    Keywords:  METTL3; SNHG3; gastric cancer; growth; m6A; miR-186
    DOI:  https://doi.org/10.1177/03946320231204694
  7. Nat Commun. 2023 Oct 10. 14(1): 6334
    CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes.
    Yanfen Zheng, Xingyang Li, Shuang Deng, Hongzhe Zhao, Ying Ye, Shaoping Zhang, Xudong Huang, Ruihong Bai, Lisha Zhuang, Quanbo Zhou, Mei Li, Jiachun Su, Rui Li, Xiaoqiong Bao, Lingxing Zeng, Rufu Chen, Jian Zheng, Dongxin Lin, Chuan He, Jialiang Zhang, Zhixiang Zuo.
      N6-methyladenosine (m6A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m6A profiling in 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 m6A peaks with 195 hyper-methylated and 93 hypo-methylated in PDAC compared with adjacent normal tissues. The differential m6A modifications distinguish two PDAC subtypes with different prognosis outcomes. The formation of the two subtypes is driven by a newly identified m6A regulator CSTF2 that co-transcriptionally regulates m6A installation through slowing the RNA Pol II elongation rate during gene transcription. We find that most of the CSTF2-regulated m6As have positive effects on the RNA level of host genes, and CSTF2-regulated m6As are mainly recognized by IGF2BP2, an m6A reader that stabilizes mRNAs. These results provide a promising PDAC subtyping strategy and potential therapeutic targets for precision medicine of PDAC.
    DOI:  https://doi.org/10.1038/s41467-023-41861-y
  8. Cell Death Discov. 2023 Oct 10. 9(1): 371
    IGF2BP2 acts as a m6A modification regulator in laryngeal squamous cell carcinoma through facilitating CDK6 mRNA stabilization.
    Xiaojun Tang, Qinglai Tang, Shisheng Li, Mengmeng Li, Tao Yang.
      Laryngeal squamous cell carcinoma (LSCC) is one of the most commonly seen cancers in the head and neck region with increasing morbidity and mortality globally. N6-methyladenosine (m6A) modification plays a critical role in the carcinogenesis of LSCC. In this study, two datasets from online database were analyzed for differentially expressed genes (DEGs) between LSCC and normal samples. Furthermore, we carried out a series of experiments, including hematoxylin & eosin staining, immunohistochemical (IHC) staining, CCK-8, colony formation, transwell, flow cytometry, xenograft tumor model assays, actinomycin D assay, cycloheximide (CHX) assay, methylated m6A RNA immunoprecipitation (Me-RIP), RNA immunoprecipitation (RIP) assay, to verify the relevant findings in vivo and in vitro. Insulin like growth factor 2 mRNA binding protein 2 (IGF2BP2) was identified as an up-regulated m6A regulator in LSCC samples. Lower IGF2BP2 expression was linked to higher survival probability in LSCC and other head and neck squamous cell carcinoma patients. In LSCC cells, IGF2BP2 knockdown attenuated cancer cell aggressiveness, possibly through modulating cell cycle arrest. In the xenograft tumor model derived from IGF2BP2 knocked-down LSCC cells, IGF2BP2 knockdown inhibited tumor growth. IGF2BP2 up-regulated CDK6 expression through facilitating the stability of CDK6 mRNA and protein. CDK6 knockdown caused no changes in IGF2BP2 expression, but partially eliminated the promotive effects of IGF2BP2 overexpression on LSCC cells' aggressiveness. Overexpressed IGF2BP2 in LSCC serves as an oncogenic factor, promoting LSCC cell proliferation and invasion in vitro and tumor growth in a xenograft tumor model in vivo through facilitating CDK6 mRNA stabilization.
    DOI:  https://doi.org/10.1038/s41420-023-01669-7
  9. Mol Biotechnol. 2023 Oct 13.
    Crosstalk Between m6A RNA Methylation and miRNA Biogenesis in Cancer: An Unholy Nexus.
    P J Jayasree, Shalmoli Dutta, Pragati Karemore, Piyush Khandelia.
      N6-methyladenosine (m6A) is one of the most prevalent internal reversible chemical modification of RNAs in eukaryotes, which has attracted widespread attention recently owing to its regulatory roles in a plethora of normal developmental processes and human diseases like cancer. Deposition of the m6A mark on RNAs is mediated by the dynamic interplay between m6A regulatory proteins such as m6A RNA methyltransferases (m6A writers), m6A RNA demethylases (m6A erasers) and m6A RNA binding proteins (m6A readers). m6A regulators are ectopically expressed in various cancer types, often leading to aberrant expression of tumor-suppressor and oncogenic mRNAs either directly or indirectly via regulating the biogenesis of non-coding RNAs like miRNAs. miRNAs are tiny regulators of gene expression, which often impact various hallmarks of cancer and thus influence tumorigenesis. It is becoming increasingly clear that m6A RNA modification impacts biogenesis and function of miRNAs, and recent studies have interestingly, uncovered many miRNAs whose biogenesis and function are regulated by m6A writers, erasers and readers. In this review, we discuss various mechanisms by which m6A RNA methylation regulates miRNA biogenesis, the functional crosstalk between m6A RNA methylation and miRNAs and how it modulates various aspects of tumorigenesis. The potential of m6A RNA methylation regulated miRNAs as biomarkers and novel therapeutic targets to treat various cancers is also addressed.
    Keywords:  Cancer; Gene expression; Precursor miRNA; Primary miRNA; m6A RNA methylation; miRNAs
    DOI:  https://doi.org/10.1007/s12033-023-00921-w
  10. Heliyon. 2023 Sep;9(9): e19816
    The m6A reader YTHDC1-mediated lncRNA CTBP1-AS2 m6A modification accelerates cholangiocarcinoma progression.
    Zhe Jin, Yahui Liu.
      Background: Cholangiocarcinoma (CCA) is a serious malignancy originating from the bile ducts and the second most common primary liver cancer. Long non-coding RNA (lncRNA) is a functional lncRNA that plays an important role in human cancers. However, the role and underlying mechanisms of CTBP1-AS2 in CCA remain unknown.Purpose: In this study, we investigated the functional role and mechanism of long-stranded non-coding RNA (lncRNA) C-terminal binding protein 1 antisense RNA 2 (CTBP1-AS2) in CCA progression.
    Result: In the present study, the bioinformatics analysis revealed that YTHDC1 and CTBP1-AS2 were significantly upregulated, and it was confirmed in cholangiocarcinoma tissues from CCA patients. Meanwhile, we demonstrated that knockdown of YTHDC1 or lncRNA CTBP1-AS2 inhibited CCA cell proliferation, migration and invasion, blocked the cell cycle in G2/M phase and promoted apoptosis of CCA cells. In addition, lncRNA CTBP1-AS2-mediated N6-methyladenosine (m6A) methylation levels were significantly elevated in cholangiocarcinoma tissues, whereas knockdown of YTHDC1 resulted in a significant down-regulation of m6A methylation levels by lncRNA CTBP1-AS2.
    Conclusion: Our results suggest that YTHDC1 affects cholangiocarcinoma progression by modifying the lncRNA CTBP1-AS2 m6A, and CTBP1-AS2 may be a promising therapeutic target for CCA.
    Keywords:  CTBP1-AS2; Cholangiocarcinoma; Mediated N6-methyladenosine (m6A); YTHDC1
    DOI:  https://doi.org/10.1016/j.heliyon.2023.e19816
  11. J Environ Pathol Toxicol Oncol. 2024 ;43(1): 45-60
    Comprehensive Investigation of m6A Regulators for Prognosis in Head and Neck Squamous Cell Carcinoma.
    Jingning Cheng, Yong Lyu, Ziyan Cheng.
      The early detection of head and neck squamous cell carcinoma (HNSCC) has an important impact on the clinical prognosis. N6-methyladenosine (m6A) is involved in the post-transcriptional regulation of tumorigenesis and development. In this study, the prognosis and biological functions of m6A regulator targets in HNSCC were explored. RNA-Seq expression data and clinical information from TCGA-HNSCC and GSE23036 datasets were collected. The mRNA levels of IGF2BP2 and IGF2BP3 in tumor tissues were significantly up-regulated. Differential expression and functional enrichment analysis of potential targets for IGF2BP2 and IGF2BP3 obtained from the m6A2Target database showed that they were significantly enriched in cell cycle-related pathways. The Cox regression analysis was performed to establish a three-mRNA signature including PLAU, LPIN1 and AURKA. The prognostic effect was verified in the external dataset GSE41613. Further studies revealed that the three-mRNA signature was significantly associated with survival in the clinical subgroup. The ROC curve, Harrell consistency index and decision curve comparison used to compare the predictive effect of the three-mRNA signature and the other signatures in previous studies showed that the three-mRNA signature had better predictive effect on the prognosis of HNSCC patients. The three-mRNA signature expression were verified in HNSCC cell lines with qRT-PCR and Western blot. Sequence analysis showed that m6A-modification sites existed on PLAU, LPIN1 and AURKA genes. In conclusion, the three-mRNA signature has been proved to be useful on evaluating the prognosis and contributing to the personalized treatment of HNSCC, and IGB2BP2/3 were related to the cell cycle in HNSCC.
    DOI:  https://doi.org/10.1615/JEnvironPatholToxicolOncol.2023047701
  12. Genomics. 2023 Oct 09. pii: S0888-7543(23)00169-6. [Epub ahead of print] 110725
    Dynamic alterations of the transcriptome-wide m6A methylome in cytogenetically normal acute myeloid leukaemia during initial diagnosis and relapse.
    Jinjing Zhang, Tong Liu, Yue Wang, Xiaojing Yan, Yan Li, Feng Xu, Rui Zhang.
      Accumulating studies have indicated that N6-methyladenosine (m6A) plays an important role in acute myeloid leukaemia (AML). However, little is known about the m6A methylome at a transcriptome-wide scale in AML patients. We obtained three pairs of bone marrow (BM) samples from cytogenetically normal AML patients at the timepoints of diagnosis (AML) and relapse (R_AML) and three BM samples from healthy donors used as normal controls (NCs). Methylated RNA immunoprecipitation next-generation sequencing (MeRIP-Seq) was conducted to identify differences in the m6A methylomes between AML and NC and between R_AML and AML. We identified a total of 11,076 and 11,962 differential m6A peaks in AML and R_AML group, respectively. These dysregulated m6A peaks were detected on all chromosomes, especially chr1, chr19 and chr17, and were mainly enriched in 3' untranslated regions, stop codon and coding sequence regions. Moreover, GO and KEGG analyses indicated that m6A -modified genes were significantly enriched in cancer-related biological functions and pathways. Additionally, we identified a link between the m6A methylome and RNA transcriptome via combined analyses of MeRIP-seq and RNA-seq data. In addition, 5 genes, HSPG2, HOMER3, TSPO2, CXCL12 and FUT1 regulated by m6A modification potentially, were shown to be related to the prognosis of AML patients. Additionally, we detected the mRNA expression of major m6A regulators and potential target mRNA on the leukemogenesis and found that the expression of IGF2BP2, HSPG2 and HOMER3 were upregulated in AML at the time of diagnosis. Moreover, their expression became downregulated after remission and then elevated again at relapse. Our study provides the first data on the differential m6A methylome in AML patients during initial diagnosis and relapse. This study demonstrates a novel relationship between m6A modification and AML relapse and paves the way for further studies aimed at elucidating the epigenic mechanisms involved in the relapse of AML.
    Keywords:  Acute myeloid leukaemia; MeRIP-seq; RNA-seq; Relapse; m(6)A
    DOI:  https://doi.org/10.1016/j.ygeno.2023.110725
  13. Mol Biotechnol. 2023 Oct 10.
    N6-Methyladenosine (m6A) Reader IGF2BP1 Accelerates Gastric Cancer Development and Immune Escape by Targeting PD-L1.
    Bingxi Tang, Lei Bi, Yanbin Xu, Lili Cao, Xinli Li.
      N6-methyladenosine (m6A) functions as an important regulator in various human cancers, including gastric cancer. The immunotherapy targeting PD-1/PD-L1 has brought hope for advanced gastric cancer therapeutic. Here, present research aims to investigate the roles of m6A reader IGF2BP1 on gastric cancer tumor development and immune escape. Results indicated that IGF2BP1 up-regulated in the gastric cancer tissue and correlated with poor prognosis of gastric cancer patients. IGF2BP1 overexpression augmented the proliferation of co-cultured gastric cancer cells, and mitigated the CD8+ T cells mediated anti-tumor response, including IFN-γ secretion, surface PD-L1 level, and cytotoxicity of CD8+ T cells. Meanwhile, IGF2BP1 silencing exerted the opposite effects. In silico analysis revealed that there was a remarkable m6A modified site on PD-L1 mRNA. Moreover, the IGF2BP1 overexpression enhanced the stability of PD-L1 mRNA, thereby deteriorating the immune escape of gastric cancer cells. Collectively, these results describe a novel regulatory mechanism of IGF2BP1 by regulating PD-L1 through m6A epigenetic modification, which might provide insights for gastric cancer immunotherapies.
    Keywords:  Gastric cancer; IGF2BP1; Immune escape; N6-methyladenosine; PD-L1
    DOI:  https://doi.org/10.1007/s12033-023-00896-8
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