bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒08‒14
twenty papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. The Emerging Role of RNA N6-Methyladenosine Modification in Pancreatic Cancer.
  2. Rational Design and Optimization of m6A-RNA Demethylase FTO Inhibitors as Anticancer Agents.
  3. The role of N6-methyladenosine methylation in environmental exposure-induced health damage.
  4. FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m6A dependent pathway.
  5. A signature based on m6A pattern and tumor microenvironment infiltration in clear cell renal cell carcinoma.
  6. The S. cerevisiae m6A-reader Pho92 promotes timely meiotic recombination by controlling key methylated transcripts.
  7. m6A modification-mediated BATF2 suppresses metastasis and angiogenesis of tongue squamous cell carcinoma through inhibiting VEGFA.
  8. N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma.
  9. METTL3 inhibits inflammation of retinal pigment epithelium cells by regulating NR2F1 in an m6A-dependent manner.
  10. N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer.
  11. Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury.
  12. Intermittent hypoxia-induced METTL3 downregulation facilitates MGLL-mediated lipolysis of adipocytes in OSAS.
  13. Cromolyn chitosan nanoparticles reverse the DNA methylation of RASSF1A and p16 genes and mitigate DNMT1 and METTL3 expression in breast cancer cell line and tumor xenograft model in mice.
  14. Research Progress on Long Noncoding RNAs and N6-Methyladenosine in Hepatocellular Carcinoma.
  15. Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming.
  16. RNA m6A modification orchestrates the rhythm of immune cell development from hematopoietic stem cells to T and B cells.
  17. Comprehensive analysis of RNA m6A methylation in pressure overload-induced cardiac hypertrophy.
  18. Comprehensive Analysis of SLC17A9 and Its Prognostic Value in Hepatocellular Carcinoma.
  19. M6A-related lncRNAs predict clinical outcome and regulate the tumor immune microenvironment in hepatocellular carcinoma.
  20. Oxidative stress regulates cardiomyocyte energy metabolism through the IGF2BP2-dynamin2 signaling pathway.
  1. Front Oncol. 2022 ;12 927640
    The Emerging Role of RNA N6-Methyladenosine Modification in Pancreatic Cancer.
    Xiaoge Hu, Xiangxiang Lei, Jinhui Guo, Wen Fu, Wen Sun, Qiliang Lu, Wei Su, Qiuran Xu, Kangsheng Tu.
      Pancreatic cancer (PC) is one of the most common malignant cancers, ranking the seventh highest causes of cancer-related deaths globally. Recently, RNA N6-methyladenosine (m6A) is emerging as one of the most abundant RNA modifications in eukaryote cells, involved in multiple RNA processes including RNA translocation, alternative splicing, maturation, stability, and degradation. As reported, m6A was dynamically and reversibly regulated by its "writers", "erasers", and "readers", Increasing evidence has revealed the vital role of m6A modification in the development of multiple types of cancers including PC. Currently, aberrant m6A modification level has been found in both PC tissues and cell lines. Moreover, abnormal expressions of m6A regulators and m6A-modified genes have been reported to contribute to the malignant development of PC. Here in this review, we will focus on the function and molecular mechanism of m6A-modulated RNAs including coding RNAs as well as non-coding RNAs. Then the m6A regulators will be summarized to reveal their potential applications in the clinical diagnosis, prognosis, and therapeutics of PC.
    Keywords:  N6-methyladenosine (m6A); RNA methylation; coding RNAs; non-coding RNAs; pancreatic cancer
    DOI:  https://doi.org/10.3389/fonc.2022.927640
  2. J Med Chem. 2022 Aug 08.
    Rational Design and Optimization of m6A-RNA Demethylase FTO Inhibitors as Anticancer Agents.
    Sarah Huff, Indrasena Reddy Kummetha, Lingzhi Zhang, Lingling Wang, William Bray, Jiekai Yin, Vanessa Kelley, Yinsheng Wang, Tariq M Rana.
      Aberrant regulation of N6-methyladenosine (m6A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m6A demethylase fat mass- and obesity-associated protein (FTO), which removes both m6A and N6,2'-O-dimethyladenosine (m6Am) RNA modifications. In this work, we describe the rational design and optimization of a new class of FTO inhibitors derived from our previous lead FTO-04 with nanomolar potency and high selectivity against the homologous m6A RNA demethylase ALKBH5. The oxetanyl class of compounds comprise competitive inhibitors of FTO with potent antiproliferative effects in glioblastoma, acute myeloid leukemia, and gastric cancer models where lead FTO-43 demonstrated potency comparable to clinical chemotherapeutic 5-fluorouracil. Furthermore, FTO-43 increased m6A and m6Am levels in a manner comparable to FTO knockdown in gastric cancer cells and regulated Wnt/PI3K-Akt signaling pathways. The oxetanyl class contains significantly improved anticancer agents with a variety of applications beyond glioblastoma.
    DOI:  https://doi.org/10.1021/acs.jmedchem.1c02075
  3. Environ Sci Pollut Res Int. 2022 Aug 11.
    The role of N6-methyladenosine methylation in environmental exposure-induced health damage.
    Yanlu Feng, Tong Liu, Siyi Xu, Yiyi Ren, Yiling Ge, Lihong Yin, Yuepu Pu, Geyu Liang.
      The health risks caused by environmental pollution have long been of substantial concern. With the development of epigenetics, a large number of studies have demonstrated that N6-methyladenosine (m6A) modification is involved in the regulation of various important life activities associated with various diseases. Recent studies have revealed that m6A plays a key role in health damage caused by environmental exposure by regulating post-transcriptional gene expression. Therefore, our study outlined the effects of environmental pollutant exposure on m6A methylation and its regulator levels. Moreover, we found that m6A methylation modifications were involved in the development of various health damages by regulating important life activities in vivo, such as reactive oxygen species imbalance, apoptosis, epithelial-mesenchymal transition (EMT), and inflammatory processes. More importantly, we delved into the regulatory mechanisms of m6A methylation dysregulation in environmental pollution-induced diseases. Finally, by examining the published literature, we found that methyltransferase-like protein 3 (METTL3) and fat mass- and obesity-associated protein (FTO) were potentially used as biomarkers of health damage induced by particulate matter exposure and heavy metal exposure, respectively. The current studies on regulators of METTL3 and FTO were more promising to bring new perspectives for the treatment of environmental health-related diseases.
    Keywords:  Biological function; Biomarker; Environmental pollutants; FTO; Health damage; METTL3; m6A
    DOI:  https://doi.org/10.1007/s11356-022-22093-x
  4. Cell Death Discov. 2022 Aug 12. 8(1): 356
    FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m6A dependent pathway.
    Haixiang Shen, Yufan Ying, Xueyou Ma, Haiyun Xie, Shiming Chen, Jiazhu Sun, Zixiang Liu, Chao Wen, Zitong Yang, Xiao Wang, Mingjie Xu, Jindan Luo, Ben Liu, Jiangfeng Li, Xiangyi Zheng, Liping Xie.
      FTO, as an m6A mRNA demethylase, is involved in various cancers. However, the role of FTO in clear cell renal cell carcinoma (ccRCC) remains unclear. In the present study, we discovered FTO is upregulated in ccRCC. Functionally, knockdown of FTO significantly impairs the proliferation and migration ability of ccRCC cells. Mechanistically, our data suggest FTO promotes the proliferation and migration of ccRCC through preventing degradation of PDK1 mRNA induced by YTHDF2 in an m6A-dependent mechanism. Overall, our results identify the protumorigenic role of FTO through the m6A/YTHDF2/PDK1 pathway, which could be a promising therapeutic target for ccRCC.
    DOI:  https://doi.org/10.1038/s41420-022-01151-w
  5. Am J Transl Res. 2022 ;14(7): 4931-4947
    A signature based on m6A pattern and tumor microenvironment infiltration in clear cell renal cell carcinoma.
    Chen Yang, Tian Yu, Qingwen Li, Fang Xie, Qin Lin.
      BACKGROUND: RNA N6-methyladenosine (m6A) has been found to have a critical impact on clear cell renal cell carcinoma (ccRCC) by affecting the tumor microenvironment (TME) and immune cell (IC) infiltration and is related to the treatment and survival rate of patients with ccRCC. However, the mechanism of m6A in TME and IC infiltration remained unclear.METHODS: Nonnegative Matrix Factorization (NMF) clustering was performed on 650 ccRCC cases from the Cancer Genome Atlas (TCGA) and the Gene-Expression Omnibus (GEO) datasets. The immune infiltration was generated by the single-sample gene-set enrichment analysis (ssGSEA) algorithm. Survival analyses were performed using the Kaplan-Meier method, and the significance of the differences was determined using the log-rank test. The m6A score was constructed based on the expression of m6A regulators to quantify m6A modification. The package "survminer R" was employed to layer patients' low and high scores groups and predict the immunotherapy response.
    RESULTS: Three different patterns of m6A modification were established, and significant differences in TME and IC infiltration features were found in these three patterns. Survival analysis demonstrated that m6A cluster A and m6A gene cluster A experienced a longer survival time. Evaluation of m6A modification patterns in individual tumors was initiated by the m6A score. The low m6A score subtype was characterized by increased tumor mutation burden (TMB) and immune infiltration, whereas a high m6A score with a lack of immune cell infiltration showed significantly better overall survival. m6A score was also associated with the expression of programmed cell death protein 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Patients in the high m6A score group had high PD-L1 expression and low CTLA-4 expression. Significant differences in prognosis were identified among types of different TMB and m6A scores, where low TMB and high m6A score had longer survival time.
    CONCLUSIONS: This research indicated that m6A modification greatly affected TME and IC infiltration. Physicians can develop practical immunotherapy strategies for patients with ccRCC by evaluating m6A-associated genes.
    Keywords:  ccRCC; immunotherapy; m6A; tumor microenvironment; tumor mutation burden
  6. Nucleic Acids Res. 2022 Aug 08. pii: gkac640. [Epub ahead of print]
    The S. cerevisiae m6A-reader Pho92 promotes timely meiotic recombination by controlling key methylated transcripts.
    Jérémy Scutenaire, Damien Plassard, Mélody Matelot, Tommaso Villa, Julie Zumsteg, Domenico Libri, Bertrand Séraphin.
      N6-Methyladenosine (m6A), one of the most abundant internal modification of eukaryotic mRNAs, participates in the post-transcriptional control of gene expression through recruitment of specific m6A readers. In Saccharomyces cerevisiae, the m6A methyltransferase Ime4 is expressed only during meiosis and its deletion impairs this process. To elucidate how m6A control gene expression, we investigated the function of the budding yeast m6A reader Pho92. We show that Pho92 is an early meiotic factor that promotes timely meiotic progression. High-throughput RNA sequencing and mapping of Pho92-binding sites following UV-crosslinking reveal that Pho92 is recruited to specific mRNAs in an m6A-dependent manner during the meiotic prophase, preceding their down-regulation. Strikingly, point mutations altering m6A sites in mRNAs targeted by Pho92 are sufficient to delay their down-regulation and, in one case, to slow down meiotic progression. Altogether, our results indicate that Pho92 facilitate the meiotic progression by accelerating the down-regulation of timely-regulated mRNAs during meiotic recombination.
    DOI:  https://doi.org/10.1093/nar/gkac640
  7. Cell Cycle. 2022 Aug 10. 1-17
    m6A modification-mediated BATF2 suppresses metastasis and angiogenesis of tongue squamous cell carcinoma through inhibiting VEGFA.
    Haojie Wen, Jinyong Tang, Yi Cui, Minhua Hou, Juan Zhou.
      The aim is to explore the underlying mechanism of basic leucine zipper ATF-like transcription factor 2 (BATF2) in tongue squamous cell carcinoma (TSCC). The expression of BATF2 in TSCC tissues and corresponding adjacent normal TSCC tissues, human TSCC cell lines (SCC-15 and CAL-27) and human normal tongue epithelial cells NTEC was detected. Then, SCC-15 cells with stable BATF2 knockdown and CAL-27 cells with BATF2 overexpression were established to investigate the functional effect of BATF2 on TSCC. Thereafter, the effect of BATF2 on TSCC angiogenesis and BATF2 m6A methylation was also examined. BATF2 was significantly downregulated in TSCC tissues and cell lines, and BATF2 overexpression could suppress growth, metastasis and angiogenesis of TSCC. Mechanistically, vascular endothelial growth factor A (VEGFA) was identified as a downstream gene of BATF2, and it was confirmed that BATF2 suppressed growth, metastasis and angiogenesis of TSCC via inhibiting VEGFA. In addition, the N6-methyladenosine (m6A) modification of BATF2 mRNA mediated by METTL14 suppressed its expression in TSCC. METTL14/BATF2 axis could serve as a novel promising therapeutic candidate against angiogenesis for TSCC.
    Keywords:  BATF2; Tongue squamous cell carcinoma; VEGFA; angiogenesis; cell metastasis; m6A
    DOI:  https://doi.org/10.1080/15384101.2022.2109897
  8. Front Genet. 2022 ;13 872186
    N6-methyladenosine RNA methylation regulator-related alternative splicing gene signature as prognostic predictor and in immune microenvironment characterization of patients with low-grade glioma.
    Aierpati Maimaiti, Abudireheman Tuersunniyazi, Xianghong Meng, Yinan Pei, Wenyu Ji, Zhaohai Feng, Lei Jiang, Zengliang Wang, Maimaitijiang Kasimu, Yongxin Wang, Xin Shi.
      Background: N6-methyladenosine (m6A) RNA methylation is an important epigenetic modification affecting alternative splicing (AS) patterns of genes to regulate gene expression. AS drives protein diversity and its imbalance may be an important factor in tumorigenesis. However, the clinical significance of m6A RNA methylation regulator-related AS in the tumor microenvironment has not been investigated in low-grade glioma (LGG). Methods: We used 12 m6A methylation modulatory genes (WTAP, FTO, HNRNPC, YTHDF2, YTHDF1, YTHDC2, ALKBH5, YTHDC1, ZC3H13, RBM15, METTL14, and METTL3) from The Cancer Genome Atlas (TCGA) database as well as the TCGA-LGG (n = 502) dataset of AS events and transcriptome data. These data were downloaded and subjected to machine learning, bioinformatics, and statistical analyses, including gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Univariate Cox, the Least Absolute Shrinkage and Selection Operator (LASSO), and multivariable Cox regression were used to develop prognostic characteristics. Prognostic values were validated using Kaplan-Maier survival analysis, proportional risk models, ROC curves, and nomograms. The ESTIMATE package, TIMER database, CIBERSORT method, and ssGSEA algorithm in the R package were utilized to explore the role of the immune microenvironment in LGG. Lastly, an AS-splicing factor (SF) regulatory network was examined in the case of considering the role of SFs in regulating AS events. Results: An aggregate of 3,272 m6A regulator-related AS events in patients with LGG were screened using six machine learning algorithms. We developed eight AS prognostic characteristics based on splice subtypes, which showed an excellent prognostic prediction performance. Furthermore, quantitative prognostic nomograms were developed and showed strong validity in prognostic prediction. In addition, prognostic signatures were substantially associated with tumor immune microenvironment diversity, ICB-related genes, and infiltration status of immune cell subtypes. Specifically, UGP2 has better promise as a prognostic factor for LGG. Finally, splicing regulatory networks revealed the potential functions of SFs. Conclusion: The present research offers a novel perspective on the role of AS in m6A methylation. We reveal that m6A methylation regulator-related AS events can mediate tumor progression through the immune-microenvironment, which could serve as a viable biological marker for clinical stratification of patients with LGG so as to optimize treatment regimens.
    Keywords:  alternative splicing; gene signature; low-grade glioma; machine learning; prognosis; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fgene.2022.872186
  9. Front Immunol. 2022 ;13 905211
    METTL3 inhibits inflammation of retinal pigment epithelium cells by regulating NR2F1 in an m6A-dependent manner.
    Jiayu Meng, Xianyang Liu, Shiyun Tang, Yusen Liu, Chenyang Zhao, Qian Zhou, Na Li, Shengping Hou.
      N6-metyladenosine (m6A) RNA methylation has been proven to be involved in diverse biological processes, but its potential roles in the development of lipopolysaccharide (LPS) induced retinal pigment epithelium (RPE) inflammation have not been revealed. In this study, we explored the effects and underlying mechanisms of methyltransferase-like 3 (METTL3) in LPS stimulated RPE cells. Proliferation of METTL3-silenced RPE cells was examined by Cell counting kit-8 (CCK8) and 5-Ethynyl-2´-Deoxyuridine (Edu). Expression of tight junction proteins ZO-1 and Occludin, and secretion of inflammatory factors interleukins (IL)-1, 6 and 8 were detected by Western blotting or Enzyme-linked immunosorbent assay (ELISA). RNA sequencing and methylated RNA immunoprecipitation (MeRIP) sequencing were used to analyze the target gene nuclear receptor subfamily 2 group F member 1 (NR2F1) of METTL3. Our results showed that both human RPE (hRPE) cells and ARPE19 cells exhibited inhibited proliferation, tight junction protein expression, and increased inflammatory factor secretion after METTL3 silencing. Mechanistically, we found that NR2F1, as a METTL3-methylated target gene, inhibits Occludin level and promotes IL-6 secretion of RPE cells in an m6A-dependent manner. Interestingly, NR2F1 deficiency reversed the decreased Occludin expression and increased IL-6 secretion in METTL3-defective RPE cells. In conclusion, our study revealed that METTL3 attenuates RPE cell inflammation by methylating NR2F1, suggesting the critical role of METTL3 in RPE cells.
    Keywords:  M6A; METTL3; NR2F1; RPE; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.905211
  10. Cell Biosci. 2022 Aug 08. 12(1): 125
    N6-methyladenosine-mediated CELF2 regulates CD44 alternative splicing affecting tumorigenesis via ERAD pathway in pancreatic cancer.
    Shihui Lai, Yan Wang, Ting Li, Yihong Dong, Yihao Lin, Liang Wang, Shangeng Weng, Xiang Zhang, Chengjie Lin.
      BACKGROUND: Alternative splicing (AS) of genes has been found to affect gene stability, and its abnormal regulation can lead to tumorigenesis. CELF2 is a vital splicing factor to participate in mRNA alternative splicing. Its downregulation has been confirmed to promote the occurrence and development of pancreatic cancer (PC). However, the regulatory role and mechanisms in PC has not been elucidated.RESULTS: CELF2 was downregulated in PC tissues, which affected tumor TNM stage and tumor size, and low expression of CELF2 indicated a poor prognosis of PC. In vivo and in vitro experiments showed that abnormal expression of CELF2 affected the stemness, apoptosis, and proliferation of PC cells. Furthmore, we also found that CELF2 was targeted by ALKBH5 for m6A modification, leading to CELF2 degradation by YTHDF2. Bioinformatic analysis of AS model based on the TCGA database indicated that CELF2 could target CD44 to form different spliceosomes, thereby affecting the biological behavior of PC cells. The conversion of CD44s to CD44V is the key to tumorigenesis. Transcriptomic analysis was conducted to reveal the mechanism of CELF2-mediated CD44 AS in PC. We found that CELF2-mediated splicing of CD44 led to changes in the level of endoplasmic reticulum stress, further regulating the endoplasmic reticulum-associated degradation (ERAD) signaling pathway, thereby affecting apoptosis and cell stemness. In addition, ERAD signaling pathway inhibitor, EerI, could effectively reverse the effect of CD44 on tumors.
    CONCLUSIONS: This study indicates that N6-methyladenosine-mediated CELF2 promotes AS of CD44, affecting the ERAD pathway and regulating the biological behavior of PC cells. CELF2 is expected to be a new target for targeted-drug development.
    Keywords:  Alternative splicing; CELF2; ERAD pathway; N6-methyladenosine (m6A); Pancreatic cancer (PC)
    DOI:  https://doi.org/10.1186/s13578-022-00844-0
  11. Ann Transl Med. 2022 Jul;10(13): 737
    Transcriptomic analysis and laboratory experiments reveal potential critical genes and regulatory mechanisms in sepsis-associated acute kidney injury.
    Boyang Liu, Shengxiang Ao, Fang Tan, Wei Ma, Haoru Liu, Huaping Liang, Xia Yang, Xinjin Chi.
      Background: Sepsis-associated acute kidney injury (SA-AKI) is one of the most frequent and serious complications of sepsis. However, the transcriptional regulatory network of the pathophysiological mechanism of the kidney has not been revealed. This study identified new mechanisms in SA-AKI using bioinformatics analyses and laboratory-based experiments.Methods: We performed transcriptomic profiling of mouse kidneys after cecal ligation and puncture (CLP) to mimic clinical sepsis. RNA from kidney samples from the CLP and control groups was isolated and analyzed using bulk messenger RNA (mRNA)-seq. Differentially expressed genes (DEGs) between the two groups were identified, and GO, KEGG and GSEA pathway enrichment analyses were performed. The protein-protein interaction (PPI) network of DEGs and hub genes was analyzed. The hub genes were verified using quantitative real-time polymerase chain reaction (qPCR) or Western blotting. The interaction network, targeted microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) of hub genes were predicted, and the critical miRNA-hub gene regulatory axis was verified using qPCR, Western blotting, malondialdehyde (MDA) determination and flow cytometry. Correlation analyses of N6-adenosine methylation (m6A) RNA methylation regulators and hub genes and m6A modification analysis were performed.
    Results: A total of 4,754 DEGs were identified between the two groups using high-throughput sequencing. The pathways in which DEGs were enriched included ferroptosis (the highest enrichment score), apoptosis, and the PI3K-Akt, NF-kappa B and IL-17 signaling pathways. Seven (Hmox1, Spp1, Socs3, Mapk14, Lcn2, Cxcl1 and Cxcl12) of the 15 hub genes were involved in the KEGG pathway. mmu-miR-7212-5p-Hmox1 was a key RNA regulatory axis in ferroptosis. m6A RNA methylation modifications were involved in SA-AKI. The correlation analyses showed the close interactions among the m6A RNA methylation regulators and important hub genes.
    Conclusions: The findings of this study provide new insights into the mechanism regulating the occurrence and progression of SA-AKI. The mmu-miR-7212-5p-Hmox1 axis in ferroptosis and m6A RNA methylation regulators may have potential clinical significance for the future treatment of SA-AKI. The datasets generated for this study can be found in the repository of the GEO database (Series number: GSE186822).
    Keywords:  N6-adenosine methylation RNA methylation (m6A RNA methylation); Sepsis; acute kidney injury (AKI); bioinformatics analysis; ferroptosis
    DOI:  https://doi.org/10.21037/atm-22-845
  12. Cell Death Discov. 2022 Aug 06. 8(1): 352
    Intermittent hypoxia-induced METTL3 downregulation facilitates MGLL-mediated lipolysis of adipocytes in OSAS.
    Xiuji Huang, Xuming Huang, Haiyan Guo, Jin Li, Chunxia Zhou, Yuanli Huang, Chunliu Lai, Wan Zeng, Xiaozhen Tan, Lihong Niu, Hui Li, Jian Qi, Canmao Xie.
      Intermittent hypoxia (IH) is the core pathological feature of obstructive sleep apnea syndrome (OSAS), and insulin resistance (IR) is the most common metabolic complication of OSAS. Studies have shown that the levels of free fatty acids (FFAs), which are mainly released from adipocytes by lipolysis, are elevated in OSAS and play an important role in the development of IR. However, whether and how IH regulates adipocyte lipolysis in OSAS is not clear. Here, we revealed that the apnea hypopnea index was positively correlated with the serum levels of FFAs and FFA release from adipocytes in OSAS. In addition, IH facilitated lipolysis and FFA release from adipocytes by downregulating the level of METTL3. METTL3 downregulation impaired N6-methyladenosine (m6A) levels in MGLL mRNA and reduced MGLL expression, thereby promoting lipolysis. In addition, we identified YTHDF2 as the m6A reader that interacts with MGLL mRNA, accelerating its degradation. Furthermore, our data showed reduced levels of METTL3 and elevated levels of MGLL in the adipose tissues of OSAS patients and indicated an effect of METTL3 on lowering FFA levels and improving IR in rats with chronic IH. In conclusion, our study provides new insights into the development and treatment of IR in OSAS.
    DOI:  https://doi.org/10.1038/s41420-022-01149-4
  13. Chem Biol Interact. 2022 Aug 09. pii: S0009-2797(22)00299-X. [Epub ahead of print] 110094
    Cromolyn chitosan nanoparticles reverse the DNA methylation of RASSF1A and p16 genes and mitigate DNMT1 and METTL3 expression in breast cancer cell line and tumor xenograft model in mice.
    Tarek K Motawi, Shohda A El-Maraghy, Dina Sabry, Omina M Nady, Mahmoud A Senousy.
      BACKGROUND: Developing epigenetic drugs for breast cancer (BC) remains a novel therapeutic approach. Cromolyn is a mast cell stabilizer emerging as an anticancer drug; its encapsulation in chitosan nanoparticles (CSNPs) improves its effect and bioavailability. However, its effect on DNA and RNA methylation machineries has not been previously tackled.METHODS: the possible anticancer effect of cromolyn CSNPs and its potential as an epigenetic drug was investigated in vitro using MCF-7 human BC cell line and in vivo using Ehrlich ascites carcinoma-xenograft model in mice symbolizing murine mammary adenocarcinoma. Mice were injected with a single dose of Ehrlich ascites carcinoma cells subcutaneously for the induction of tumor mass, and then randomized into three groups: control, cromolyn CSNPs (equivalent to 5 mg cromolyn/kg, i.p.) and plain CSNPs twice/week for 2 weeks.
    RESULTS: cromolyn CSNPs showed prominent anticancer effect in MCF-7 cells by reducing the cell viability percent and enhancing DNA damage in the comet assay demonstrating its apoptotic actions. Mechanistically, cromolyn CSNPs influenced potential epigenetic processes through mitigating DNA methyltransferase 1 (DNMT1) expression, reversing the hypermethylation pattern of the tumor suppressor RASSF1A and p16 genes and attenuating the expression of the RNA N6-methyladenosine writer, methyltransferase-like 3 (METTL3). Cromolyn CSNPs diminished ERK1/2 phosphorylation, a possible arm influencing DNMT1 expression. In vivo, cromolyn CSNPs lessened the tumor volume and halted DNMT1 and METTL3 expression in Ehrlich carcinoma mice.
    CONCLUSIONS: cromolyn CSNPs have the premise as an epigenetic drug through inhibiting ERK1/2 phosphorylation/DNMT1/DNA methylation and possibly impacting the RNA methylation machinery via mitigating METTL3 expression.
    Keywords:  Breast cancer; Cromolyn; DNMT; METTL3; Nanoparticles; RNA methylation
    DOI:  https://doi.org/10.1016/j.cbi.2022.110094
  14. Front Oncol. 2022 ;12 907399
    Research Progress on Long Noncoding RNAs and N6-Methyladenosine in Hepatocellular Carcinoma.
    Wenjie Zhang, Wenlong Wu, Qiang Meng, Long Yang, Juzheng Yuan, Zelin Tian, Rui Ding, Xuan Zhang, Jianlin Wang, Kaishan Tao.
      N6-methyladenosine (m6A) is an epigenetic modification that widely exists in long noncoding RNAs (lncRNAs) and is involved in the regulation of oncogenes or tumor suppressor genes that form complex enzymes to affect the occurrence of tumors. The abnormal modification of m6A methylation can alter the overall m6A level and thus contribute to the malignant biological behaviors of hepatocellular carcinoma (HCC). LncRNAs related to m6A methylation are involved in lipogenesis, the proliferation, migration and invasion of HCC cells, the stemness of tumor cells and sorafenib resistance. In this review, we systematically elaborated the occurrence mechanism of lncRNA and m6A methylation modification in HCC and the effect of m6A methylation modification of lncRNA on the occurrence of HCC, suggesting that the combination of m6A methylation modification and lncRNA will be more meaningful as molecular markers or prognostic markers. It is helpful to provide further ideas for exploring the pathogenesis of HCC and identifying new targets for HCC treatment and diagnosis and achieve precise individual treatment of liver cancer.
    Keywords:  N6-methyladenosine; epigenetic modification; hepatocellular carcinoma; long noncoding RNAs; methylation modification
    DOI:  https://doi.org/10.3389/fonc.2022.907399
  15. Stem Cell Reports. 2022 Aug 09. pii: S2213-6711(22)00370-8. [Epub ahead of print]17(8): 1799-1809
    Mettl14-driven senescence-associated secretory phenotype facilitates somatic cell reprogramming.
    Chenxiang Xi, Jiatong Sun, Xiaocui Xu, You Wu, Xiaochen Kou, Yanhong Zhao, Jiacheng Shen, Yu Dong, Kang Chen, Zhongqu Su, Dan Liu, Wen Ye, Yingdong Liu, Ran Zhang, Yiliang Xu, Hong Wang, Lujiang Hao, Li Wu, Shaorong Gao.
      The METTL3-METTL14 complex, the "writer" of N6-methyladenosine (m6A), plays an important role in many biological processes. Previous studies have shown that Mettl3 overexpression can increase the level of m6A and promote somatic cell reprogramming. Here, we demonstrate that Mettl14, another component of the methyltransferase complex, can significantly enhance the generation of induced pluripotent stem cells (iPSCs) in an m6A-independent manner. In cooperation with Oct4, Sox2, Klf4, and c-Myc, overexpressed Mettl14 transiently promoted senescence-associated secretory phenotype (SASP) gene expression in non-reprogrammed cells in the late stage of reprogramming. Subsequently, we demonstrated that interleukin-6 (IL-6), a component of the SASP, significantly enhanced somatic cell reprogramming. In contrast, blocking the SASP using a senolytic agent or a nuclear factor κB (NF-κB) inhibitor impaired the effect of Mettl14 on reprogramming. Our results highlight the m6A-independent function of Mettl14 in reprogramming and provide new insight into the interplay between senescence and reprogramming in vitro.
    Keywords:  Mettl14; m(6)A methylation; reprogramming; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1016/j.stemcr.2022.06.012
  16. Front Immunol. 2022 ;13 839291
    RNA m6A modification orchestrates the rhythm of immune cell development from hematopoietic stem cells to T and B cells.
    Chuanxiang Zhao, Guoying Xu, Xiaoxian Zhang, Yunfeng Ye, Weili Cai, Qixiang Shao.
      RNA, one of the major building blocks of the cell, participates in many essential life processes. RNA stability is well-established to be closely related to various RNA modifications. To date, hundreds of different RNA modifications have been identified. N6-methyladenosine (m6A) is one of the most important RNA modifications in mammalian cells. An increasing body of evidence from recently published studies suggests that m6A modification is a novel immune system regulator of the generation and differentiation of hematopoietic stem cells (HSCs) and immune cells. In this review, we introduce the process and relevant regulatory mechanisms of m6A modification; summarize recent findings of m6A in controlling HSC generation and self-renewal, and the development and differentiation of T and B lymphocytes from HSCs; and discuss the potential mechanisms involved.
    Keywords:  B cell; N6-methyladenosine; RNA; T cell; hematopoietic stem cell
    DOI:  https://doi.org/10.3389/fimmu.2022.839291
  17. BMC Genomics. 2022 Aug 11. 23(1): 576
    Comprehensive analysis of RNA m6A methylation in pressure overload-induced cardiac hypertrophy.
    Weidong Li, Chenxv Xing, Limeng Bao, Shengna Han, Tianxia Luo, Zhiju Wang, Hongkun Fan.
      AIM: To analyze and compare the mRNA N6-methyladenosine modifications in transverse aortic constriction induced mice hearts and normal mice hearts.MATERIALS AND METHODS: Colorimetric quantification was used to probe the changes in m6A modifications in the total RNA. The expression of m6A-related enzymes was analyzed via qRT-PCR and western blotting. RNA-seq and MeRIP-seq were performed to identify genes with differences in m6A modifications or expression in the transcriptome profile.
    RESULTS: Compared with the control group, the TAC group exhibited higher m6A methylation levels. FTO and WTAP were downregulated after TAC, while METTL3 was significantly downregulated at the protein level. MeRIP-seq revealed that 1179 m6A peaks were upmethylated and 733 m6A peaks were downmethylated, and biological analysis of these genes exhibited a strong relationship with heart function.
    CONCLUSION: Our findings provide novel information regarding m6A modification and gene expression changes in cardiac hypertrophy, which may be fundamental for further research.
    Keywords:  Cardiac hypertrophy; MeRIP-seq; m6A transcriptome
    DOI:  https://doi.org/10.1186/s12864-022-08833-w
  18. Front Oncol. 2022 ;12 809847
    Comprehensive Analysis of SLC17A9 and Its Prognostic Value in Hepatocellular Carcinoma.
    Xue-Yan Kui, Yan Gao, Xu-Sheng Liu, Jing Zeng, Jian-Wei Yang, Lu-Meng Zhou, Xiao-Yu Liu, Yu Zhang, Yao-Hua Zhang, Zhi-Jun Pei.
      Background: Solute carrier family 17 member 9 (SLC17A9) encodes a member of a family of transmembrane proteins that are involved in the transport of small molecules. SLC17A9 is involved in the occurrence and development of various cancers, but its biological role in liver hepatocellular carcinoma (LIHC) is unclear.Methods: The expression level of SLC17A9 was assessed using The Cancer Genome Atlas (TCGA) database and immunohistochemistry of tumor tissues and adjacent normal liver tissues. The receiver operating characteristic (ROC) and R software package performed diagnosis and prognosis. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes functional enrichment and co-expression of SLC17A9, gene-gene interaction (GGI), and protein-protein interaction (PPI) networks were performed using R, GeneMANIA, and STRING. Western blot, real-time quantitative PCR (RT-qPCR), immunofluorescence, colony formation, wound scratch assay, ATP production assays, and high connotation were applied to determine the effect of SLC17A9 knockdown on HEPG2 (hepatocellular liver carcinoma) cells. TIMER, GEPIA, and TCGA analyzed the relationship between SLC17A9 expression and immune cells, m6A modification, and ferroptosis.
    Results: SLC17A9 expression in LIHC tissues was higher than in normal liver tissues (p < 0.001), and SLC17A9 was related to sex, DSS (disease-specific survival), and PFI (progression-free interval) (p = 0.015, 0.006, and 0.023). SLC17A9 expression has diagnostic (AUC: 0.812; CI: 0.770-0.854) and prognostic potential (p = 0.015) in LIHC. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) functional enrichment analysis showed that SLC17A9 was closely related to neuronal cell body, presynapse, axonogenesis, PI3K/Akt signaling pathway. GGI showed that SLC17A9 was closely related to MYO5A. PPI showed that SLC17A9 was closely related to SLC18A3. SLC17A9 silencing inhibited HepG2 cells proliferation, migration, colony formation, and reduced their ATP level. SLC17A9 expression level was related to immune cells: B cells (r = 0.094, P = 8.06E-02), CD4+ T cells (r = 0.184, P = 5.95E-04), and macrophages (r = 0.137, P = 1.15E-02); m6A modification: HNRNPC (r = 0.220, p < 0.001), METTL3 (r = 0.180, p < 0.001), and WTAP (r = 0.130, p = 0.009); and ferroptosis: HSPA5 (r = 0.240, p < 0.001), SLC7A11 (r = 0.180, p < 0.001), and FANCD2 (r = 0.280, p < 0.001).
    Conclusion: Our data show that SLC17A9 may influence LIHC progression. SLC17A9 expression correlates with tumor immune infiltration, m6A modification, and ferroptosis in LIHC and may have diagnostic and prognostic value in LIHC.
    Keywords:  SLC17A9; TCGA; ferroptosis; hepatocellular carcinoma; immune infiltration; m6A modification
    DOI:  https://doi.org/10.3389/fonc.2022.809847
  19. BMC Cancer. 2022 Aug 09. 22(1): 867
    M6A-related lncRNAs predict clinical outcome and regulate the tumor immune microenvironment in hepatocellular carcinoma.
    Bo Chen, Zhan Yang, Zhichao Lang, Qiqi Tao, Rongrong Zhang, Yating Zhan, Xuantong Xu, Kai Zhu, Jianjian Zheng, Zhengping Yu, Suhui Yu.
      LncRNA N6-methylandenosine (m6A) modification has been shown to be associated with the constitution of the tumor microenvironment (TME) and tumorigenesis. It's essential to understand the mechanisms of lncRNA m6A modification in hepatocellular carcinoma (HCC) and identify relative prognostic predictors to guide therapy and explore potential therapeutic targets. Pearson correlation analysis was performed to identify m6A-related lncRNAs in 374 patients with HCC. Unsupervised cluster analysis of the potential m6A-related lncRNA-based HCC subtypes was conducted, followed by the concurrent analysis of their relationship with TME characteristics, immune checkpoints, immune features, and prognosis through single sample gene set enrichment analysis and ESTIMATE algorithm. Cox regression analyses were performed to screen prognostic m6A-related lncRNA, construct an m6A-related lncRNA signature (m6A-RLRS), and establish an integrated nomogram for the prognosis of patients with HCC. We identified 61 m6A-related lncRNAs and two HCC subtypes defined by consensus cluster of m6A-related lncRNAs with distinct clinical features. Progression-free survival (PFS), three TME-related scores, 15 immune-associated gene sets, and two immune checkpoints expression were found to be significantly different among the two subtypes. Twenty-five prognostic m6A-related lncRNAs were determined, four of which were included to establish an m6A-RLRS with favorable discrimination, and the signature was validated in the validation set and an independent FAHWMU cohort (n = 60). Furthermore, a novel nomogram combining signature and clinical predictors was generated with a C-index of 0.703, and an original ceRNA regulatory network consisting of 9 lncRNAs, 28 miRNAs, and 75 target mRNAs was constructed. Finally, the differential expression of four m6A-related lncRNA was verified by qRT-PCR. In conclusion, m6A-related lncRNA prognostic signature and molecular subtype contributes to accurately predict the prognosis of HCC and provide potential novel therapeutic targets.
    Keywords:  Hepatocellular carcinoma; Long noncoding RNA; N6-methylandenosine; Prognosis; Tumor microenvironment; ceRNA network
    DOI:  https://doi.org/10.1186/s12885-022-09925-2
  20. Biochem Biophys Res Commun. 2022 Jul 31. pii: S0006-291X(22)01066-X. [Epub ahead of print]624 134-140
    Oxidative stress regulates cardiomyocyte energy metabolism through the IGF2BP2-dynamin2 signaling pathway.
    Juncheng Wang, Shan Li, Huajiong Yu, Danchen Gao.
      BACKGROUND: Over the past few decades, numerous clinical and experimental studies have confirmed that oxidative stress is enhanced in heart failure (HF). We recently found that inhibition of highly expressed dynamin2 can protect myocardial ischemia-reperfusion injury in mice and inhibit oxidative stress in ischemic cardiomyocytes. However, the specific mechanisms are still not fully understood. In this study, we hypothesized that oxidative stress induces cardiomyocyte apoptosis through IGF2BP2 regulation, which is regulated through the dynamin2 expression.METHODS: H2O2-treated cardiomyocytes were observed for the regulatory effect of reactive oxygen species (ROS) on IGF2BP2 and the effect of IGF2BP2 on dynamin2 gene expression was determined by lentiviral-mediated IGF2BP2 overexpression. Then, siRNA knockdown of dynamin2 was used to observe whether it can alter the effect of IGF2BP2 on myocardial cells. Finally, IGF2BP2 was knocked down in ischemic rats using shRNA to determine the effects of IGF2BP2 on myocardial ischemia.
    RESULTS: ROS can promote dynamin2 expression by inducing IGF2BP2 expression and dynamin2 knockdown could reduce the injury of IGF2BP2 to cardiomyocytes. Inhibition of IGF2BP2 expression in myocardial ischemic rats ameliorated cardiac fibrosis in ischemic myocardium.
    CONCLUSION: Oxidative stress can induce cardiomyocyte apoptosis through the IGF2BP2-dynamin2 pathway. Inhibition of IGF2BP2 expression significantly improves the fibrosis and remodeling that occurs in ischemic myocardium.
    Keywords:  Dynamin2; Heart failure; IGF2BP2; Ischemia injury; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbrc.2022.07.089
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