bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022–03–13
eightteen papers selected by
Sk Ramiz Islam, Saha Institute of Nuclear Physics
  1. N6-methyladenosine (m6A) RNA modification in tumor immunity.
  2. Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA.
  3. The Role of m6A Regulator-Mediated Methylation Modification and Tumor Microenvironment Infiltration in Glioblastoma Multiforme.
  4. Methyltransferase-like 3 induces the development of cervical cancer by enhancing insulin-like growth factor 2 mRNA-binding proteins 3-mediated apoptotic chromatin condensation inducer 1 mRNA stability.
  5. The effect of N6-methyladenosine (m6A) factors on the development of acute respiratory distress syndrome in the mouse model.
  6. METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma.
  7. Decreased RNA m6A methylation enhances the process of the epithelial mesenchymal transition and vasculogenic mimicry in glioblastoma.
  8. Comprehensive characterization of m6A methylation and its impact on prognosis, genome instability, and tumor microenvironment in hepatocellular carcinoma.
  9. PGM1 and ENO1 Promote the Malignant Progression of Bladder Cancer via Comprehensive Analysis of the m6A Signature and Tumor Immune Infiltration.
  10. m6 A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels.
  11. Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA.
  12. A novel inhibitor of N 6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities.
  13. m5 C and m6 A Modification of Long Noncoding NKILA Accelerates Cholangiocarcinoma Progression via miR-582-3p-YAP1 axis.
  14. m6A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells.
  15. PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification.
  16. Expression profiling of N6-methyladenosine modified circRNAs in acute myeloid leukemia.
  17. Identification of the Expression Patterns and Potential Prognostic Role of 5-Methylcytosine Regulators in Hepatocellular Carcinoma.
  18. Expression profile, clinical significance and biological functions of IGF2BP2 in esophageal squamous cell carcinoma.
  1. Cancer Biol Med. 2022 Mar 08. pii: j.issn.2095-3941.2021.0534. [Epub ahead of print]
    N6-methyladenosine (m6A) RNA modification in tumor immunity.
    Siyi Zheng, Hui Han, Shuibin Lin.
      Growing evidence supports that cancer progression is closely associated with the tumor microenvironment and immune evasion. Importantly, recent studies have revealed the crucial roles of epigenetic regulators in shaping the tumor microenvironment and restoring immune recognition. N6-methyladenosine (m6A) modification, the most prevalent epigenetic modification of mammalian mRNAs, has essential functions in regulating the processing and metabolism of its targeted RNAs, and therefore affects various biological processes including tumorigenesis and progression. Recent studies have demonstrated the critical functions and molecular mechanisms underlying abnormal m6A modification in the regulation of tumor immunity. In this review, we summarize recent research progress in the potential roles of m6A modification in tumor immunoregulation, with a special focus on the anti-tumor processes of immune cells and involvement in immune-associated molecules and pathways. Furthermore, we review current knowledge regarding the close correlation between m6A-related risk signatures and the tumor immune microenvironment landscape, and we discuss the prognostic value and therapeutic efficacy of m6A regulators in a variety of cancer types.
    Keywords:  N6-methyladenosine (m6A) modification; immune cells; immune evasion; tumor immunology; tumor microenvironment (TME)
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0534
  2. Front Oncol. 2022 ;12 824258
    Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA.
    Yize Li, Hongyan Peng, Peng Jiang, Jiarui Zhang, Yongmei Zhao, Xuelian Feng, Cui Pang, Jingyi Ren, Hongmei Zhang, Wendong Bai, Wenchao Liu.
      Altered expression levels of the proteins that regulate N6-methyladenosine (m6A) RNA methylation, including methyltransferase-like 14 (METTL14), are associated with cancer development. Based on our analysis of m6A methylation regulators using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, we focused on the regulatory role of METTL14 in ovarian cancer. We performed bioinformatics and survival analyses with these datasets and also used METTL14-overexpressing SKOV-3 ovarian cancer cells for in vitro studies. Trophinin associated protein (TROAP) siRNA and treatment with or without actinomycin D was used in the cells for qRT-PCR, western blot, cDNA microarray, cell viability, colony formation, luciferase gene reporter, methylated RNA immunoprecipitation (MeRIP)-qPCR, total RNA methylation, and RNA stability assays. Additionally, ovarian cancer and normal tissue samples were analyzed by immunohistochemistry, qRT-PCR, and western blot assays. The TCGA and GEO data confirmed copy number variations (CNVs) of these m6A RNA methylation regulators in ovarian cancer tissues. Furthermore, reduced METTL14 expression was associated with alterations in CNVs as well as poor patient survival in ovarian cancer. Moreover, the METTL14 and m6A RNA methylation levels were both significantly reduced in ovarian cancer tissues than in normal tissues. Restoration of METTL14 expression suppresses ovarian cancer cell proliferation by inhibition of TROAP expression. Further in vivo and in vitro experiments confirmed that METTL14 is a negative regulator of ovarian cancer cell proliferation via TROAP expression and that m6A RNA methylation regulates TROAP mRNA stability. In conclusion, METTL14 overexpression decreased ovarian cancer proliferation by inhibition of TROAP expression via an m6A RNA methylation-dependent mechanism.
    Keywords:  Copy number variations; METTL14; Ovarian cancer; TROAP; m6A RNA methylation
    DOI:  https://doi.org/10.3389/fonc.2022.824258
  3. Front Cell Dev Biol. 2022 ;10 842835
    The Role of m6A Regulator-Mediated Methylation Modification and Tumor Microenvironment Infiltration in Glioblastoma Multiforme.
    Liang Wang, Haiyan Cao, Ying Zhong, Peigang Ji, Fan Chen.
      N6-methyladenosine (m6A) RNA methylation is an emerging epigenetic modification in recent years and epigenetic regulation of the immune response has been demonstrated, but the potential role of m6A modification in GBM tumor microenvironment (TME) cell infiltration and stemness remain unknown. The m6A modification patterns of 310 GBM samples were comprehensively evaluated based on 21 m6A regulators, and we systematically correlated these modification patterns with TME cell infiltration characteristics and stemness characteristics. Construction of m6Ascore to quantify the m6A modification patterns of individual GBM samples using a principal component analysis algorithm. We identified two distinct patterns of m6A modification. The infiltration characteristics of TME cells in these two patterns were highly consistent with the immunophenotype of the GBM, including the immune activation differentiation pattern and the immune desert dedifferentiation pattern. We also identified two modes of regulation of immunity and stemness by m6A methylation. Stromal activation and lack of effective immune infiltration were observed in the high m6Ascore subtype. Pan-cancer analysis results illustrate a significant correlation between m6AScore and tumor clinical outcome, immune infiltration, and stemness. Our work reveals that m6A modifications play an important role in the development of TME and stemness diversity and complexity. Patients with a low m6AScore showed significant therapeutic advantages and clinical benefits. Assessing the m6A modification pattern of individual tumors will help enhance our knowledge of TME infiltration and stemness characteristics, contribute to the development of immunotherapeutic strategies.
    Keywords:  GBM; TME; m6A; methylation; novel immunotherapy; pan-cancer
    DOI:  https://doi.org/10.3389/fcell.2022.842835
  4. Bioengineered. 2022 Mar;13(3): 7034-7048
    Methyltransferase-like 3 induces the development of cervical cancer by enhancing insulin-like growth factor 2 mRNA-binding proteins 3-mediated apoptotic chromatin condensation inducer 1 mRNA stability.
    Cuihong Su, Yan Zhang, Ping Chen, Wei Yang, Jiaqiu Du, Danfeng Zhang.
      N6-methyladenosine (m6A) plays a critical role in the tumorigenesis of cervical cancer (CC). Here, we aimed to investigate the potential role of methyltransferase-like 3 (METTL3) in CC. Gene expression was determined via real-time quantitative polymerase chain reaction. Cellular functions were detected using colony formation, 5-ethynyl-2'-deoxyuridine (EdU), and Transwell assays. The interactions among METTL3, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), and apoptotic chromatin condensation inducer 1 (ACIN1) were confirmed using the MeRIP and RIP assays. An in vivo assay was performed to verify the role of METTL3 in CC development. METTL3 is overexpressed in CC, and therefore, its knockdown inhibits the proliferation and migration of CC cells. Silencing METTL3 inhibits tumor growth in vivo. Moreover, a positive association was observed between METTL3 and ACIN1. METTL3 interacts with IGF2BP3 to promote the mRNA stability of ACIN1, the overexpression of which induces the aggressiveness of CC cells. METTL3 promotes ACIN1 mRNA stability to accelerate CC progression, implying that METTL3 is a promising biomarker in CC.
    Keywords:  ACIN1; Cervical cancer; IGF2BP3; METTL3; N6-methyladenosine
    DOI:  https://doi.org/10.1080/21655979.2022.2044261
  5. Bioengineered. 2022 Mar;13(3): 7622-7634
    The effect of N6-methyladenosine (m6A) factors on the development of acute respiratory distress syndrome in the mouse model.
    Liming Fei, Gengyun Sun, Juan Sun, Dong Wu.
      Acute respiratory distress syndrome (ARDS) can cause loss of alveolar-capillary membrane integrity and life-threatening immune responses. The underlying molecular mechanisms of ARDS remain unclear. N6-methyladenosine (m6A)-RNA modification plays an important part in many biological processes. However, it is not clear whether ARDS alters RNA methylation in lung tissue. We tried to investigate the changes of m6A-RNA methylation in lung tissues of lipopolysaccharide (LPS)-induced ARDS mice. Lung tissue samples were collected to detect the expression of m6A factors through hematoxylin and eosin (HE) staining, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemical analysis and western blot. The overall m6A levels in lung tissue of ARDS in mouse were detected by UPLC-UV-MS. HE staining showed that the degree of the inflammatory response was more severe in the LPS-3 h group. The mRNA expression of YTHDF1, YTHDC1 and IGFBP3 was remarkably up-regulated at, respectively, 6, 6 and 12 h after LPS treatment. The mRNA expression of METTL16, FTO, METTL3, KIAA1429, RBM15, ALKBH5, YTHDF2, YTHDF3, YTHDC2 and IGFBP2 was significantly down-regulated at 24 h after LPS treatment. The protein expression of METTL16 and FTO increased, YTHDC1, IGFBP3 YTHDF1 and YTHDF3 showed a down-regulation trend after LPS induction. Overall m6A-RNA methylation levels were significantly increased at 6 h after LPS induction. In ARDS mice, LPS-induced m6A methylation may be involved in the expression regulation of inflammatory factors and may play important roles in the occurrence and development of lung tissue. It is suggested that m6A modification may be a promising therapeutic target for ARDS.
    Keywords:  Acute respiratory distress syndrome; RNA methylation; inflammatory response; lung; m6A
    DOI:  https://doi.org/10.1080/21655979.2022.2049473
  6. Br J Cancer. 2022 Mar 05.
    METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma.
    Lili Zhang, Xiaofang Luo, Sen Qiao.
       BACKGROUND: Clear-cell renal-cell carcinoma (ccRCC) is one of the leading causes of tumour-related death worldwide. Methyltransferase-like 14 (METTL14) is reported to regulate m6A modification in cancers. The aim of this study is to investigate the biological function and molecular mechanism of METTL14 in the pathogenesis of ccRCC.
    METHODS: Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were used to detect the expression of METTL14 and Pten. METTL14 overexpression or knockdown was used in the in vitro and in vivo studies to investigate the biological functions of METTL14. m6A-RNA immunoprecipitation and RNA immunoprecipitation were used to investigate the m6A modification mediated by METTL14.
    RESULTS: METTL14 expression was significantly down-regulated in ccRCC tissues. Functionally, upregulation of METTL14 inhibited ccRCC cells proliferation and migration in vitro. METTL14 overexpression significantly inhibited the activation of the phosphoinositide 3 kinase (PI3K)/AKT signalling pathway. Furthermore, phosphate and tension homology deleted on chromosome ten (Pten) is a target of METTL14. Overexpression of METTL14 increased the m6A enrichment of Pten, and promoted Pten expression. METTL14-enhanced Pten mRNA stability was dependent on YTHDF1.
    CONCLUSIONS: METTL14-mediated m6A modification of Pten mRNA inhibited tumour progression, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for ccRCC.
    DOI:  https://doi.org/10.1038/s41416-022-01757-y
  7. Am J Cancer Res. 2022 ;12(2): 893-906
    Decreased RNA m6A methylation enhances the process of the epithelial mesenchymal transition and vasculogenic mimicry in glioblastoma.
    Min Tao, Xiaoyu Li, Lei He, Xiaoming Rong, Hongxuan Wang, Jingrui Pan, Zijing Lu, Xiaoni Zhang, Ying Peng.
      RNA N6-methyladenosine (m6A) modification is gradually thought to be an active participant in the considerable biological processes of glioblastoma (GB), providing us with a novel insight for exploring this disease. However, the role of RNA m6A modification during the epithelial mesenchymal transition (EMT) or vasculogenic mimicry (VM) progression has not been investigated in GB. Here we performed a research to validate the impact exerted by AlkB homolog 5 (ALKBH5), one of "erasers" for RNA m6A and methyltransferase-like 3 (METTL3) which adds m6A modification to the RNAs on the progression of EMT and VM in GB. In this study, we demonstrate that the m6A levels of RNAs were reduced in GB cells and glioma tissues. Patients with high mRNA expression of ALKBH5 acquired relatively shorter median overall survival (OS) time, while patients with relatively high expression of MEETL3 prolonged their disease free survival. ALKBH5 enhanced GB cell proliferation and influenced cell cycle in vitro. Decreased RNA m6A methylation enhanced the progression of the EMT and VM in glioblastoma cells. ALKBH5 strengthened glioblastoma growth and enhanced the EMT and VM process of glioblastoma in vivo. Our study uncovers that RNA m6A methylation suppresses the process of EMT and VM in glioblastoma, providing a new perspective to seek for a potential therapeutic target for GB.
    Keywords:  ALKBH5; Glioblastoma; METTL3; RNA m6A methylation; epithelial mesenchymal transition; vasculogenic mimicry
  8. BMC Med Genomics. 2022 Mar 08. 15(1): 53
    Comprehensive characterization of m6A methylation and its impact on prognosis, genome instability, and tumor microenvironment in hepatocellular carcinoma.
    Tengfei Yin, Lang Zhao, Shukun Yao.
       BACKGROUND: N6-methyladenosine (m6A) RNA regulation was recently reported to be important in carcinogenesis and cancer development. However, the characteristics of m6A modification and its correlations with clinical features, genome instability, tumor microenvironments (TMEs), and immunotherapy responses in hepatocellular carcinoma (HCC) have not been fully explored.
    METHODS: We systematically analyzed the m6A regulator-based expression patterns of 486 patients with HCC from The Cancer Genome Atlas and Gene Expression Omnibus databases, and correlated these patterns with clinical outcomes, somatic mutations, TME cell infiltration, and immunotherapy responses. The m6A score was developed by principal component analysis to evaluate m6A modifications in individual patients.
    RESULTS: M6A regulators were dysregulated in HCC samples, among which 18 m6A regulators were identified as risk factors for prognosis. Three m6A regulator-based expression patterns, namely m6A clusters, were determined among HCC patients by m6A regulators with different m6A scores, somatic mutation counts, and specific TME features. Additionally, three distinct m6A regulator-associated gene-based expression patterns were also identified based on prognosis-associated genes that were differentially expressed among the three m6A clusters, showing similar properties as the m6A regulator-based expression patterns. Higher m6A scores were correlated with older age, advanced stages, lower overall survival, higher somatic mutation counts, elevated PD-L1 expression levels, and poorer responses to immune checkpoint inhibitors. The m6A score was validated as an independent and valuable prognostic factor for HCC.
    CONCLUSION: M6A modification is correlated with genome instability and TME in HCC. Evaluating m6A regulator-based expression patterns and the m6A score of individual tumors may help identify candidate biomarkers for prognosis prediction and immunotherapeutic strategy selection.
    Keywords:  Genome instability; Hepatocellular carcinoma; M6A modification; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12920-022-01207-x
  9. J Oncol. 2022 ;2022 8581805
    PGM1 and ENO1 Promote the Malignant Progression of Bladder Cancer via Comprehensive Analysis of the m6A Signature and Tumor Immune Infiltration.
    Jinglin Zhao, Shu Huang, Dingji Tan, Kaiqing Yang, Mingyue Chen, Xiongfei Jia, Xiaoqin Mao.
       Background: While N6-methyladenosine (m6A) modification of RNA and the tumor immune microenvironment both influence the progression of cancer, little attention has been paid to interactions between these two factors. Thus, we systematically explored potential biomarkers in the malignant progression of bladder urothelial carcinoma (BLCA) via combining expression of m6A methylation regulators with tumor immune infiltration.
    Methods: We extracted m6A regulators from published literature, downloaded BLCA RNA-seq and clinical information from the Cancer Genome Atlas database, and integrated three main bioinformatic methods and qPCR to explore the biological variations in the malignant progression of BLCA.
    Results: FTO, IGF2BP3, and YTHDC1 have a significant difference in bladder cancer and prognosis. Two subgroups (clusters 1 and 2) were identified according to three key m6A regulators; cluster 1 was preferentially associated with poor prognosis and immune infiltration relative to cluster 2 significantly. We further identified PGM1 and ENO1 as potential prognostic biomarkers, as they were correlated with FTO and IGF2BP3 positively but with YTHDC1, negatively. M2 macrophage and TFH cells were highly infiltrated in BLCA and were associated with BLCA prognosis. Finally, PGM1 and ENO1 were correlated with M2 macrophage and TFH cells and their surface markers CD163and CXCR5.
    Conclusions: PGM1 and ENO1 are highly correlated with the malignant progression of BLCA, and the expression of these genes may be new indicators for the diagnosis and prognosis of BLCA.
    DOI:  https://doi.org/10.1155/2022/8581805
  10. Cancer Commun (Lond). 2022 Mar 09.
    m6 A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels.
    Yinan Liu, Ertao Zhai, Junting Chen, Yan Qian, Risheng Zhao, Yan Ma, Jianqiu Liu, Zhixin Huang, Shirong Cai, Jianhui Chen.
       BACKGROUND: Methyltransferase 3 (METTL3)-mediated N6-methyladenosine (m6 A) RNA modification has been demonstrated to be a potential factor in promoting gastric cancer (GC). METTL3 regulates a series of signaling pathways by modifying various mRNAs. This study aimed to identify novel METTL3-mediated signaling pathways and explored possible targets for use in the clinical setting of gastric cancer.
    METHODS: To investigate the proliferation and metastatic capacity of GC cell lines with METTL3 knockdown, a xenograft, lung metastasis, and popliteal lymph node metastasis model was used. The m6 A-modified RNA immunoprecipitation (Me-RIP) sequence was utilized to explore the target mRNAs of METTL3. Cell counting kit 8 and transwell assays were performed to investigate the promoting function of pre-B cell leukemia homeobox 1 (PBX1) and GTP cyclohydrolase 1 (GCH1). Western blotting and chromatin immunoprecipitation were employed to confirm the involvement of the METTL3-PBX1-GCH1 axis. ELISA and liquid chromatography-mass spectrometry were used to explore the biological function of tetrahydrobiopterin (BH4 ).
    RESULTS: Knockdown of METTL3 suppressed xenograft tumor growth and lung/lymph node metastasis in vivo. Mechanistically, we found that METTL3 combined with and stabilized PBX1 mRNAs. Chromatin immunoprecipitation (ChIP) and further experiments suggested that PBX1 acted as a transcription factor inducing GCH1 expression. Moreover, the METTL3-PBX1-GCH1 axis increased BH4 levels in GC cells, thereby promoting tumor progression.
    CONCLUSIONS: This study suggested that METTL3 enzymes promote tumor growth and lung/lymph node metastasis via METTL3-PBX1-GCH1 axis increasing BH4 levels in GC.
    Keywords:  BH4; GCH1; METTL3; PBX1; gastric cancer; m6A; metabolism reprogramming; metastasis; proliferation
    DOI:  https://doi.org/10.1002/cac2.12281
  11. Cancers (Basel). 2022 Mar 01. pii: 1268. [Epub ahead of print]14(5):
    Targeting IGF2BP2 Promotes Differentiation of Radioiodine Refractory Papillary Thyroid Cancer via Destabilizing RUNX2 mRNA.
    Ri Sa, Rui Liang, Xian Qiu, Ziyan He, Zhiyan Liu, Libo Chen.
      N6-methyladenosine (m6A) regulators play an important role in multiple biological and pathological processes of radioiodine refractory papillary thyroid cancer (RR-PTC). However, the function of m6A regulators in differentiation of RR-PTC remains unclear. In this study, online data, clinical samples, and RR-PTC cell lines (K1 and TPC1) were used to identify the m6A regulators that contributed to the differentiation of RR-PTC. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) was found to be associated with thyroid-specific genes in online data analyses, and metastatic PTCs with high expression of IGF2BP2 were prone to be 131I-nonavid in clinical analyses. Furthermore, targeting IGF2BP2 increased 125I uptake in RR-PTC cell lines and enhanced the sodium/iodide symporter (NIS) expression. Mechanistically, IGF2BP2 bound to the m6A modification site of runt-related transcription factor 2 (RUNX2) 3'-UTR and enhanced the RUNX2 mRNA stability. Moreover, RUNX2 could bind to the promoter region of NIS to block the differentiation of RR-PTC. Together, these results demonstrated that IGF2BP2 represents a diagnostic marker for RR-PTC, suggesting a novel differentiation therapeutic strategy of targeting IGF2BP2.
    Keywords:  IGF2BP2; RUNX2; differentiation; papillary thyroid cancer; sodium/iodide symporter
    DOI:  https://doi.org/10.3390/cancers14051268
  12. Acta Pharm Sin B. 2022 Feb;12(2): 853-866
    A novel inhibitor of N 6-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities.
    Guoyou Xie, Xu-Nian Wu, Yuyi Ling, Yalan Rui, Deyan Wu, Jiawang Zhou, Jiexin Li, Shuibin Lin, Qin Peng, Zigang Li, Hongsheng Wang, Hai-Bin Luo.
      N6-methyladenosine (m6A) modification is critical for mRNA splicing, nuclear export, stability and translation. Fat mass and obesity-associated protein (FTO), the first identified m6A demethylase, is critical for cancer progression. Herein, we developed small-molecule inhibitors of FTO by virtual screening, structural optimization, and bioassay. As a result, two FTO inhibitors namely 18077 and 18097 were identified, which can selectively inhibit demethylase activity of FTO. Specifically, 18097 bound to the active site of FTO and then inhibited cell cycle process and migration of cancer cells. In addition, 18097 reprogrammed the epi-transcriptome of breast cancer cells, particularly for genes related to P53 pathway. 18097 increased the abundance of m6A modification of suppressor of cytokine signaling 1 (SOCS1) mRNA, which recruited IGF2BP1 to increase mRNA stability of SOCS1 and subsequently activated the P53 signaling pathway. Further, 18097 suppressed cellular lipogenesis via downregulation of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), and C/EBPβ. Animal studies confirmed that 18097 can significantly suppress in vivo growth and lung colonization of breast cancer cells. Collectively, we identified that FTO can work as a potential drug target and the small-molecule inhibitor 18097 can serve as a potential agent against breast cancer.
    Keywords:  Cancer cell; FTO inhibitors; Lipogenesis; SOCS1; m6A
    DOI:  https://doi.org/10.1016/j.apsb.2021.08.028
  13. Liver Int. 2022 Mar 11.
    m5 C and m6 A Modification of Long Noncoding NKILA Accelerates Cholangiocarcinoma Progression via miR-582-3p-YAP1 axis.
    Haiming Zheng, Meiying Zhu, Wenhua Li, Zunqiang Zhou, Xinjian Wan.
      Cholangiocarcinoma (CCA) is a severe malignancy originating from the bile duct and the second most common primary liver cancer. NF-kappa B interacting lncRNA (NKILA) is functional lncRNA, which play important roles in human cancers. However, the role and underlying mechanism of NKILA in CCA remains largely unknown. Here, our study demonstrated that NKILA was significantly upregulated in CCA tissues and cells. Overexpression of NKILA associated with advanced TNM stage, lymph node and distant metastasis, and also indicated poor prognosis in CCA patients. Functionally, NKILA facilitated CCA growth and metastasis in vitro and in vivo. The 5-methylcytosine (m5 C) methyltransferase NSUN2 interacts with NKILA, increasing its m5 C level and promoting its interaction with YBX1. Moreover, NKILA physically interacted with and suppressed miR-582-3p, which was regulated by METTL3-mediated N6 -methyladenosine (m6 A) modification. Finally, we showed that YAP1 a target of NKILA via miR-582-3p and NKILA functioned partially via YAP1 in CCA. Taken together, our findings indicate a novel regulatory mechanism of NKILA for promoting CCA progression and that NKILA may be a promising target for CCA treatment.
    Keywords:  METTL3; NSUN2; RNA methylation; YAP1; ceRNA
    DOI:  https://doi.org/10.1111/liv.15240
  14. Free Radic Biol Med. 2022 Mar 03. pii: S0891-5849(22)00081-8. [Epub ahead of print]
    m6A methylation is required for dihydroartemisinin to alleviate liver fibrosis by inducing ferroptosis in hepatic stellate cells.
    Min Shen, Mei Guo, Yujia Li, Yingqian Wang, Yangling Qiu, Jiangjuan Shao, Feng Zhang, Xuefen Xu, Guoping Yin, Shijun Wang, Anping Chen, Zili Zhang, Shizhong Zheng.
      Activation of hepatic stellate cells (HSCs) is a central event in the development of liver fibrosis, and the elimination of activated HSCs is considered to be an effective anti-fibrotic strategy. Here, we report that dihydroartemisinin (DHA) prevented the activation of HSCs via ferroptosis pathway. Importantly, DHA treatment increased the level of autophagy in HSCs. The inhibition of autophagy by 3-MA dramatically abolished the DHA-induced ferroptosis in HSCs. Mechanistically, the up-regulated m6A modification is essential for the activation of autophagy by DHA through the reduction of fat mass and obesity-associated gene (FTO). Down-regulation of m6A modification by FTO overexpression could impair autophagy and the classical ferroptotic events. Interestingly, the m6A modification of BECN1 mRNA was evidently up-regulated compared with other autophagy-related genes. More importantly, YTHDF1 was identified as a key m6A reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent DHA-induced HSC ferroptosis. Noteworthy, YTH domain was essential for YTHDF1 to prolong the half-life of BECN1 mRNA in DHA-induced HSC ferroptosis. In mice, DHA treatment alleviated liver fibrosis by triggering HSC ferroptosis. HSC-specific inhibition of m6A modification and autophagy could impair DHA-induced HSC ferroptosis in murine liver fibrosis. Overall, these results provided novel implications to reveal the molecular mechanism of DHA-induced ferroptosis, by which pointed to m6A modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.
    Keywords:  Autophagy; Dihydroartemisinin; Ferroptosis; Hepatic stellate cell; Liver fibrosis; m(6)A modification
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.028
  15. Environ Pollut. 2022 Mar 05. pii: S0269-7491(22)00329-3. [Epub ahead of print] 119115
    PM2.5 induces pulmonary microvascular injury in COPD via METTL16-mediated m6A modification.
    Xiaolan Guo, Yuyin Lin, Yingnan Lin, Yue Zhong, Hongjiao Yu, Yibin Huang, Jingwen Yang, Ying Cai, FengDong Liu, Yuanyuan Li, Qian-Qian Zhang, Jianwei Dai.
      Fine particulate matter (PM2.5) exposure is a significant cause of chronic obstructive pulmonary disease (COPD), but the detailed mechanisms involved in COPD remain unclear. In this study, we established PM2.5-induced COPD rat models and showed that PM2.5 induced pulmonary microvascular injury via accelerating vascular endothelial apoptosis, increasing vascular permeability, and reducing angiogenesis, thereby contributing to COPD development. Moreover, microvascular injury in COPD was validated by measurements of plasma endothelial microparticles (EMPs) and serum VEGF in COPD patients. We then performed m6A sequencing, which confirmed that altered N6-methyladenosine (m6A) modification was induced by PM2.5 exposure. The results of a series of experiments demonstrated that the expression of methyltransferase-like protein 16 (METTL16), an m6A regulator, was upregulated in PM2.5-induced COPD rats, while the expression of other regulators did not differ upon PM2.5-induction. To clarify the regulatory effect of METTL16-mediated m6A modification induced by PM2.5 on pulmonary microvascular injury, cell apoptosis, permeability, and tube formation, the m6A level in METTL16-knockdown pulmonary microvascular endothelial cells (PMVECs) was evaluated, and the target genes of METTL16 were identified from a set of the differentially expressed and m6A-methylated genes associated with vascular injury and containing predicted sites of METTL16 methylation. The results showed that Sulfatase 2 (Sulf2) and Cytohesin-1 (Cyth1) containing the predicted METTL16 methylation sites, exhibited higher m6A methylation and were downregulated after PM2.5 exposure. Further studies demonstrated that METTL16 may regulate Sulf2 expression via m6A modification and thereby contribute to PM2.5-induced microvascular injury. These findings not only provide a better understanding of the role played by m6A modification in PM2.5-induced microvascular injury, but also identify a new therapeutic target for COPD.
    Keywords:  COPD; METTL16; PM2.5; Vascular injury; m(6)A
    DOI:  https://doi.org/10.1016/j.envpol.2022.119115
  16. Biochem Biophys Res Commun. 2022 Feb 23. pii: S0006-291X(22)00288-1. [Epub ahead of print]601 137-145
    Expression profiling of N6-methyladenosine modified circRNAs in acute myeloid leukemia.
    Mohammed Awal Issah, Dansen Wu, Feng Zhang, Weili Zheng, Yanquan Liu, Rong Chen, Guilan Lai, Jianzhen Shen.
      Acute myeloid leukemia (AML) is the most common acute leukemia in adults, associated with poor prognosis and easy relapse of disease. Circular RNAs (circRNAs) were detected to be m6A modified and the role of m6A circRNAs has been reported in other diseases including cancers, however, their role has not been elucidated in AML yet. In the present study, we aimed to investigate the expression profiling of m6A circRNAs in AML. We performed m6A circRNAs microarray analysis to identify differentially expressed m6A circRNAs in bone marrow samples from AML patients and healthy individuals (control). Furthermore, bioinformatics analysis predicted the potential functions and relevant pathways that may be associated with the m6A circRNAs. The circRNA m6A methylation levels were found to be positively associated with the circRNAs expression, suggesting circRNA m6A modification could contribute to circRNA regulation in AML. Further analysis demonstrated that circRNA m6A modification might influence the circRNA-miRNA-mRNA co-expression network that may contribute to the circRNA regulatory network in AML. Our findings provide evidence of the differential expression profile of m6A circRNAs in AML, and circRNA m6A modification may contribute to circRNA regulatory function in AML.
    Keywords:  Acute myeloid leukemia; circRNA; m(6)A modification; miRNA
    DOI:  https://doi.org/10.1016/j.bbrc.2022.02.087
  17. Front Cell Dev Biol. 2022 ;10 842220
    Identification of the Expression Patterns and Potential Prognostic Role of 5-Methylcytosine Regulators in Hepatocellular Carcinoma.
    Yong Liu, Shunzhen Zheng, Tao Wang, Ziqi Fang, Junjie Kong, Jun Liu.
      Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer with a poor prognosis. 5-methylcytosine (m5C) modification plays a nonnegligible role in tumor pathogenesis and progression. However, little is known about the role of m5C regulators in HCC. Methods: Based on 9 m5C regulators, the m5C modification patterns of HCC samples extracted from public databases were systematically evaluated and correlated with tumor immune and prognosis characteristics. An integrated model called the "m5Cscore" was constructed using principal component analysis, and its prognostic value was evaluated. Results: Almost all m5C regulators were differentially expressed between HCC and normal tissues. Through unsupervised clustering, three different m5Cclusters were ultimately uncovered; these clusters were characterized by differences in prognosis, immune cell infiltration, and pathway signatures. The m5Cscore was constructed to quantify the m5C modifications of individual patients. Subsequent analysis revealed that the m5Cscore was an independent prognostic factor of HCC and could be a novel indicator to predict the prognosis of HCC. Conclusion: This study comprehensively explored and systematically profiled the features of m5C modification in HCC. m5C modification patterns play a crucial role in the tumor immune microenvironment (TIME) and prognosis of HCC. The m5Cscore provides a more holistic understanding of m5C modification in HCC and provides a practical tool for predicting the prognosis of HCC. This study will help clinicians identify effective indicators of HCC to improve the poor prognosis of this disease.
    Keywords:  5-Methylcytosine; hepatocellular carcinoma; m5Cscore; prognosis; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.842220
  18. Exp Ther Med. 2022 Apr;23(4): 252
    Expression profile, clinical significance and biological functions of IGF2BP2 in esophageal squamous cell carcinoma.
    Fenying Lu, Weichang Chen, Tingwang Jiang, Cuie Cheng, Bin Wang, Zhiping Lu, Guojin Huang, Jiaming Qiu, Wei Wei, Ming Yang, Xia Huang.
      The ectopic expression of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) has been demonstrated to facilitate tumorigenesis and induce proliferation in a various types of cancer. However, the role of IGF2BP2 in esophageal squamous cell carcinoma (ESCC) has yet been fully elucidated. In this regard, the current study assessed the expression patterns and clinical significance of IGF2BP2 in 94 Chinese patients diagnosed with ESCC. Immunohistochemistry and reverse transcription-quantitative PCR assays were employed to assess IGF2BP2 expression in ESCC tissues compared with adjacent healthy tissues. The results revealed that the protein expression of IGF2BP2 was substantially upregulated in ESCC tissues compared with adjacent ESCC tissues. More specifically, higher IGF2BP2 expression strongly associated with tumor node metastasis stage, lymphatic infiltration and lymph node metastasis. Using two ESCC cell lines (TE-1 and TE-10), the inhibition of IGF2BP2 expression by small interfering RNA was proven to induce apoptosis and suppress proliferation, migration and cell cycle progression in vitro. Collectively, the present findings indicated that IGF2BP2 may serve a major role in the development of ESCC carcinogenesis. The present study may be helpful in the design of potential drug targets in the treatment of ESCC.
    Keywords:  downregulation; esophageal-squamous cell carcinoma; insulin-like growth factor 2 mRNA-binding protein 2; migration; proliferation
    DOI:  https://doi.org/10.3892/etm.2022.11177
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