bims-rimeca Biomed News
on RNA methylation in cancer
Issue of 2022‒03‒20
35 papers selected by
Sk Ramiz Islam
Saha Institute of Nuclear Physics
  1. N6-Methyladenosine Regulators Promote Malignant Progression of Gastric Adenocarcinoma.
  2. The methylation modification of m6A regulators contributes to the prognosis of ovarian cancer.
  3. METTL3 modulates m6A modification of CDC25B and promotes head and neck squamous cell carcinoma malignant progression.
  4. Modification of STIM2 by m6A RNA methylation inhibits metastasis of cholangiocarcinoma.
  5. m6A RNA modifications are measured at single-base resolution across the mammalian transcriptome.
  6. N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) as a Novel Mediator of Statin Effects in Human Endothelial Cells.
  7. Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer.
  8. FTO Regulates Arecoline-exposed Oral Cancer Immune Response through PD-L1.
  9. ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1.
  10. Targeting the RNA m6A modification for cancer immunotherapy.
  11. Oncogenic and tumor-suppressive functions of the RNA demethylase FTO.
  12. WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration.
  13. ALKBH5-Mediated m6A Modification of A20 Regulates Microglia Polarization in Diabetic Retinopathy.
  14. Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells.
  15. Application of m6A and TME in Predicting the Prognosis and Treatment of Clear Cell Renal Cell Carcinoma.
  16. Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer.
  17. Global profiling reveals common and distinct N6-methyladenosine (m6A) regulation of innate immune responses during bacterial and viral infections.
  18. Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Endometrioid Ovarian Cancer.
  19. RNA modification writers influence tumor microenvironment in gastric cancer and prospects of targeted drug therapy.
  20. N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis.
  21. YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m6A-dependent manner.
  22. N6-methyladenosine-related lncRNAs is a potential marker for predicting prognosis and immunotherapy in ovarian cancer.
  23. The regulatory role of N6 -methyladenosine modification in the interaction between host and microbes.
  24. PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer.
  25. Loss of m6A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression.
  26. Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.
  27. Advanced glycation end products alter the m6A-modified RNA profiles in human dermal fibroblasts.
  28. Use of High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) to Quantify Modified Nucleosides.
  29. Fat mass and obesity-associated protein promotes liver steatosis by targeting PPARα.
  30. PolyC-RNA-binding protein 1 (PCBP1) enhances tropomyosin 3 (TPM3) mRNA stability to promote the progression of esophageal squamous cell carcinoma.
  31. M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression.
  32. Structure and mechanism of the methyltransferase ribozyme MTR1.
  33. Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.
  34. Transcriptional Expressions of ALDH1A1/B1 as Independent Indicators for the Survival of Thyroid Cancer Patients.
  35. An Overview of Epigenetic Methylation in Pancreatic Cancer Progression.
  1. Front Oncol. 2021 ;11 726018
    N6-Methyladenosine Regulators Promote Malignant Progression of Gastric Adenocarcinoma.
    Yibin Zhao, Xiao Yan, Yu Wang, Juan Zhou, Yang Yu.
      N6-methyladenosine (m6A) RNA methylation is dynamically and reversibly regulated by methyltransferases, binding proteins, and demethylases. The restoration of m6A to adenosine could result in demethylation modifications. Abnormalities in m6A epigenetic modifications in cancer are of increasing interest in recent years. According to the progression and prognostic performance of m6A epigenetic modifications in gastric adenocarcinoma (STAD), this study comprehensively analyzed the m6A modification patterns of gastric adenocarcinoma specimens in The Cancer Genome Atlas (TCGA) database based on 20 m6A regulators. Here, we found that 20 m6A RNA methylation regulators were high-expressed in gastric adenocarcinoma. m6A RNA methylation regulators were closely associated with pT staging of gastric cancer. Based on such findings, we developed a prognostic model using four m6A RNA methylation regulators (IGF2BP1, RBM15, FTO, ALKBH5), and the FTO was confirmed as an independent prognostic marker.
    Keywords:  Cox regression; FTO; N6-methyladenosine (m6A); TCGA; gastric adenocarcinoma; pan-cancer; risk score
    DOI:  https://doi.org/10.3389/fonc.2021.726018
  2. Ann Transl Med. 2022 Jan;10(2): 59
    The methylation modification of m6A regulators contributes to the prognosis of ovarian cancer.
    Wenjing Zhu, Long Zhao, Beihua Kong, Ying Liu, Xin Zou, Tongqin Han, Yongmei Shi.
      Background: Ovarian cancer (OV) is the leading cause of death in gynecological cancer. The dysregulation of N6-methyladenosine (m6A) modification is commonly found in cancers. However, there is a lack of research into m6A RNA methylation regulators in OV.Methods: The RNA-Seq of 379 OV tissues and 88 healthy ovarian tissues was downloaded from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, respectively. A Gene Ontology (GO) functional analysis was performed to verify the function of m6A RNA methylation regulators. Kaplan-Meier (K-M) curves and the log-rank (Mantel-Cox) test were used for the survival analysis. A Cox regression analysis was used to identify the genes related to overall survival (OS) and build the prediction model.
    Results: m6A RNA methylation regulators were dysregulated in OV tissues compared with normal tissues (P<0.05), and patients with a high expression of KIAA1429 and YTHDC2 had a poor prognosis (P<0.05). A prognostic model was constructed based on the m6A RNA methylation regulators. Based on the risk signature, the patients were classified into high- and low-risk groups. The low-risk group's OS rate was significantly better than that of the high-risk group. The validity and accuracy of the prognostic model were verified by using TCGA and Gene Expression Omnibus (GEO) datasets, and the risk score from the prognostic model acted as an independent prognostic indicator in predicting the survival of OV patients.
    Conclusions: m6A RNA methylation regulators were dysregulated in OV tissues. More importantly, the prognostic model comprising the five selected m6A RNA methylation regulators could be a valuable tool for predicting the prognosis of OV patients.
    Keywords:  Gene Expression Omnibus (GEO); Genotype-Tissue Expression (GTEx); N6-methyladenosine (m6A); Ovarian cancer (OV); The Cancer Genome Atlas (TCGA)
    DOI:  https://doi.org/10.21037/atm-21-6462
  3. Exp Hematol Oncol. 2022 Mar 14. 11(1): 14
    METTL3 modulates m6A modification of CDC25B and promotes head and neck squamous cell carcinoma malignant progression.
    Yu-Qing Guo, Qiang Wang, Jun-Guo Wang, Ya-Jun Gu, Pan-Pan Song, Shou-Yu Wang, Xiao-Yun Qian, Xia Gao.
      BACKGROUND: N6-methyladenosine (m6A) RNA methylation and its methyltransferase METTL3 have been widely reported to be involved in different cancers by regulating RNA metabolism and function. Here, we aimed to explore the biological function and clinical significance of m6A modification and METTL3 in head and neck squamous cell carcinoma (HNSCC).METHODS: The prognostic value of METTL3 expression was evaluated using tissue microarray and immunohistochemical staining analyses in a human HNSCC cohort. The biological role and mechanism of METTL3 in HNSCC tumour growth, metastasis and angiogenesis were determined in vitro and in vivo.
    RESULTS: M6A levels and METTL3 expressions in HNSCC tissues were significantly increased compared with paired adjacent tissues. Meanwhile, METTL3 was an independent risk factor for the prognosis of HNSCC patients. Moreover, METTL3 overexpression promoted HNSCC cell proliferation, migration, invasion, and angiogenesis, while knockdown of METTL3 had an opposite effect in vivo and in vitro. Mechanistically, METTL3 enhanced the m6A modification of CDC25B mRNA, which maintained its stability and upregulated its expression, thereby activating G2/M phase of cell cycle and leading to HNSCC malignant progression.
    CONCLUSIONS: METTL3 may be a potential prognostic biomarker and therapeutic target for HNSCC.
    Keywords:  CDC25B; Cell cycle; HNSCC; METTL3; m6A
    DOI:  https://doi.org/10.1186/s40164-022-00256-3
  4. Ann Transl Med. 2022 Jan;10(2): 40
    Modification of STIM2 by m6A RNA methylation inhibits metastasis of cholangiocarcinoma.
    Feng-Qiu Chen, Hao Zheng, Ting Gu, Yu-Hua Hu, Le Yang, Zhi-Ping Huang, Guang-Lei Qiao, Hong-Jie Li.
      Background: N6-methyladenosine (m6A) is the most frequent internal methylation of eukaryotic RNA (ribonucleic acid) transcripts and plays an important function in RNA processing. The current research aimed to investigate the role of m6A-STIM2 axis in cholangiocarcinoma (CCA) progression.Methods: The expression of STIM2 (Stromal Interaction Molecule 2) in CCA was measured using quantitative polymerase chain reaction (PCR) and immunohistochemistry (IHC). STIM2 was examined in vivo for its effects on the malignant phenotypes of CCA cells. The m6A modification of STIM2 was assessed through MeRIP (methylated RNA Immunoprecipitation)-PCR.
    Results: Based on the GEPIA (Gene Expression Profiling Interactive Analysis) 2 database findings, a low STIM2 mRNA (messenger RNA) level was related to a poor prognosis in individuals with CCA. Quantitative PCR and IHC assays indicated decreased protein satin in CCA tissues and were associated with extrahepatic metastasis. Vianude mice tail vein injection model indicated that increased STIM2 levels suppressed CCA cell metastasis in vivo, while KRT8 (keratin 8) was detected as the direct downstream target of STIM2-mediated CCA cell metastasis in vivo. Meanwhile, based on SRAMP database and MeRIP assays indicated that m6A alteration resulted in abnormal STIM2 expression in CCA via METTL14 and YTHDC2.
    Conclusions: Our findings revealed the epi-transcriptomic dysregulation in CCA and metastasis by proposing a complicated STIM2-KRT8 regulatory paradigm based on m6A alteration.
    Keywords:  Intrahepatic cholangiocarcinoma; KRT8; N6-methyladenosine (m6A); STIM2; metastasis
    DOI:  https://doi.org/10.21037/atm-21-6485
  5. Nat Biotechnol. 2022 Mar 14.
    m6A RNA modifications are measured at single-base resolution across the mammalian transcriptome.
    Lulu Hu, Shun Liu, Yong Peng, Ruiqi Ge, Rui Su, Chamara Senevirathne, Bryan T Harada, Qing Dai, Jiangbo Wei, Lisheng Zhang, Ziyang Hao, Liangzhi Luo, Huanyu Wang, Yuru Wang, Minkui Luo, Mengjie Chen, Jianjun Chen, Chuan He.
      Functional studies of the RNA N6-methyladenosine (m6A) modification have been limited by an inability to map individual m6A-modified sites in whole transcriptomes. To enable such studies, here, we introduce m6A-selective allyl chemical labeling and sequencing (m6A-SAC-seq), a method for quantitative, whole-transcriptome mapping of m6A at single-nucleotide resolution. The method requires only ~30 ng of poly(A) or rRNA-depleted RNA. We mapped m6A modification stoichiometries in RNA from cell lines and during in vitro monocytopoiesis from human hematopoietic stem and progenitor cells (HSPCs). We identified numerous cell-state-specific m6A sites whose methylation status was highly dynamic during cell differentiation. We observed changes of m6A stoichiometry as well as expression levels of transcripts encoding or regulated by key transcriptional factors (TFs) critical for HSPC differentiation. m6A-SAC-seq is a quantitative method to dissect the dynamics and functional roles of m6A sites in diverse biological processes using limited input RNA.
    DOI:  https://doi.org/10.1038/s41587-022-01243-z
  6. Arterioscler Thromb Vasc Biol. 2022 Mar 17. ATVBAHA121317295
    N6-Methyladenosine Demethylase FTO (Fat Mass and Obesity-Associated Protein) as a Novel Mediator of Statin Effects in Human Endothelial Cells.
    Wentao Mo, Ziqi Chen, Xiaozhe Zhang, Gang Dai, Dongwei Ma, Jiajie Pan, Xinxia Zhang, Guifu Wu, Wendong Fan.
      BACKGROUND: N6-methyladenosine (m6A) plays a critical role in various biological processes. However, no study has addressed the role of m6A modification in the statin-induced protection of endothelial cells (ECs).METHODS: Quantitative real-time polymerase chain reaction and Western blotting analyses were used to study the expression of m6A regulatory genes in atorvastatin-treated ECs. Gain- and loss-of-function assays, methylated RNA immunoprecipitation analysis, and dual-luciferase reporter assays were performed to clarify the function of FTO (fat mass and obesity-associated protein) in ECs.
    RESULTS: Atorvastatin decreased FTO protein expression in ECs. The knockdown of FTO enhanced the mRNA and protein expression of KLF2 (Kruppel-like factor 2) and eNOS (endothelial NO synthase) but attenuated TNFα (tumor necrosis factor alpha)-induced VCAM-1 (vascular cell adhesion molecule 1) and ICAM-1 (intercellular adhesion molecule 1) expression, as well as the adhesion of monocytes to ECs. Conversely, FTO overexpression significantly upregulated the mRNA and protein levels of VCAM-1 and ICAM-1, downregulated those of KLF2 and eNOS, and strongly attenuated the atorvastatin-mediated induction of KLF2 and eNOS expression. Subsequent investigations demonstrated that KLF2 and eNOS are functionally critical targets of FTO. Mechanistically, FTO interacted with KLF2 and eNOS transcripts and regulated their expression in an m6A-dependent manner. After FTO silencing, KLF2 and eNOS transcripts with higher levels of m6A modification in their 3' untranslated regions were captured by YTHDF3 (YT521-B homology m6A RNA-binding protein 3), resulting in mRNA stabilization and the induction of KLF2 and eNOS protein expression.
    CONCLUSIONS: FTO might serve as a novel molecular target to modulate endothelial function in vascular diseases.
    Keywords:  atorvastatin; endothelial cells; luciferases; monocytes; obesity
    DOI:  https://doi.org/10.1161/ATVBAHA.121.317295
  7. Ann Transl Med. 2022 Feb;10(3): 139
    Methyltransferase-like 3 upregulation is involved in the chemoresistance of non-small cell lung cancer.
    Lin Shi, Yuxin Gong, Lin Zhuo, Siyun Wang, Shaobing Chen, Bin Ke.
      Background: Treatments for non-small cell lung cancer (NSCLC) have improved tremendously, but therapeutic resistance is a common and major clinical challenge in treatment. Methyltransferase-like 3 (METTL3) is a ribonucleic acid (RNA) methyltransferase that has crucial functions in the development and progression of cancers, including drug resistance, by regulating N6-methyladenosine (m6A) modification. However, the role of METTL3 in the progression and drug resistance of NSCLC is poorly understood.Methods: The expression levels of METTL3 and AKT serine/threonine kinase 1 (AKT1) in NSCLC tissues were detected using quantitative real-time PCR (RT-qPCR), Western blots, and immunohistochemical assays. The m6A levels of AKT1 messenger RNA (mRNA) in NSCLC tissues were detected using m6A methylated RNA immunoprecipitation-quantitative polymerase chain reaction.
    Results: The expression levels of METTL3 and the AKT1 protein were significantly increased in NSCLC tissues, and m6A expression levels of AKT1 mRNA were dramatically upregulated in NSCLC tissues. Additionally, METTL3, AKT1 protein, and m6A levels of AKT1 mRNA were overexpressed in chemoresistant NSCLC samples, and high expression levels of METTL3 and AKT1 were correlated with poor patient survival, especially in chemoresistant NSCLC patients. Further, AKT1 protein expression and m6A levels of AKT1 mRNA were positively correlated with METTL3 expression, and AKT1 protein expression was positively correlated with m6A levels of AKT1 mRNA. Moreover, METTL3 and AKT1 protein expression levels were significantly associated with cisplatin susceptibility, tumor, node, metastasis stage, and lymph node metastasis.
    Conclusions: Taken together, our results indicate that METTL3 contributes to the progression and chemoresistance of NSCLC by promoting AKT1 protein expression through regulating AKT1 mRNA m6A levels, and may provide an efficient therapeutic intervention target for overcoming chemoresistance in NSCLC.
    Keywords:  AKT serine/threonine kinase 1 (AKT1); Non-small cell lung cancer (NSCLC); biomarker; chemoresistance; methyltransferase-like 3 (METTL3)
    DOI:  https://doi.org/10.21037/atm-21-6608
  8. Cancer Sci. 2022 Mar 15.
    FTO Regulates Arecoline-exposed Oral Cancer Immune Response through PD-L1.
    Xia Li, Wuya Chen, Yijun Gao, Jing Song, Yangcong Gu, Jianming Zhang, Xiufeng Cheng, Yilong Ai.
      The high prevalence of oral squamous cell carcinoma (OSCC) in South Asia is associated with habitual areca nut chewing. Arecoline, a primary active carcinogen within areca nut extract, is known to promote OSCC pathological development. Dysregulation of N6-methyladenosine (m6A) modification has begun to emerge as a significant contributor to cancer development and progression. However, the biological effects and molecular mechanisms of m6A modification in arecoline-promoted OSCC malignance remain elusive. We reveal that chronic arecoline-exposure substantially induces upregulation of Fat mass and obesity-associated protein (FTO), MYC, and programmed cell death-ligand 1 (PD-L1) in OSCC cells. Moreover, upregulation of PD-L1 is observed in OSCC cell lines and tissues and is associated with areca nut chewing in OSCC patients. We also demonstrate that arecoline-induced FTO promotes the stability and expression levels of PD-L1 transcripts through mediating m6A modification and MYC activity, respectively. PD-L1 upregulation confers superior cell proliferation, migration, and resistance to T-cell killing to OSCC cells. Blockage of PD-L1 by administration of anti-PD-L1 antibody shrinks tumor size and improves mouse survival by elevating T-cell-mediated tumor cell killing. Therefore, targeting PD-L1 might be a potential therapeutic strategy for treating PD-L1-positive OSCC patients, especially those with habitual areca nut chewing.
    Keywords:  Arecoline; FTO; Oral Carcinoma; PD-L1; Tumor immunology
    DOI:  https://doi.org/10.1111/cas.15332
  9. Cell Mol Biol Lett. 2022 Mar 12. 27(1): 26
    ALKBH5 promotes lung fibroblast activation and silica-induced pulmonary fibrosis through miR-320a-3p and FOXM1.
    Wenqing Sun, Yan Li, Dongyu Ma, Yi Liu, Qi Xu, Demin Cheng, Guanru Li, Chunhui Ni.
      BACKGROUND: N6-methyladenosine (m6A) is the most common and abundant internal modification of RNA. Its critical functions in multiple physiological and pathological processes have been reported. However, the role of m6A in silica-induced pulmonary fibrosis has not been fully elucidated. AlkB homolog 5 (ALKBH5), a well-known m6A demethylase, is upregulated in the silica-induced mouse pulmonary fibrosis model. Here, we sought to investigate the function of ALKBH5 in pulmonary fibrosis triggered by silica inhalation.METHODS: We performed studies with fibroblast cell lines and silica-induced mouse pulmonary fibrosis models. The expression of ALKBH5, miR-320a-3p, and forkhead box protein M1 (FOXM1) was determined by quantitative real-time polymerase chain reaction (qRT-PCR) analysis. RNA immunoprecipitation (RIP) assays and m6A RNA immunoprecipitation assays (MeRIP), western bolt, immunofluorescence assays, and 5-ethynyl-2'-deoxyuridine (EdU) fluorescence staining were performed to explore the roles of ALKBH5, miR-320a-3p, and FOXM1 in fibroblast activation.
    RESULTS: ALKBH5 expression was increased in silica-inhaled mouse lung tissues and transforming growth factor (TGF)-β1-stimulated fibroblasts. Moreover, ALKBH5 knockdown exerted antifibrotic effects in vitro. Simultaneously, downregulation of ALKBH5 elevated miR-320a-3p but decreased pri-miR-320a-3p. Mechanically, ALKBH5 demethylated pri-miR-320a-3p, thus blocking the microprocessor protein DGCR8 from interacting with pri-miR-320a-3p and leading to mature process blockage of pri-miR-320a-3p. We further demonstrated that miR-320a-3p could regulate fibrosis by targeting FOXM1 messenger RNA (mRNA) 3'-untranslated region (UTR). Notably, our study also verified that ALKBH5 could also directly regulate FOXM1 in an m6A-dependent manner.
    CONCLUSIONS: Our findings suggest that ALKBH5 promotes silica-induced lung fibrosis via the miR-320a-3p/FOXM1 axis or targeting FOXM1 directly. Approaches aimed at ALKBH5 may be efficacious in treating lung fibrosis.
    Keywords:  ALKBH5; FOXM1; Silicosis; m6A; miR-320a-3p
    DOI:  https://doi.org/10.1186/s11658-022-00329-5
  10. Mol Cancer. 2022 Mar 16. 21(1): 76
    Targeting the RNA m6A modification for cancer immunotherapy.
    Xinxin Li, Shoubao Ma, Youcai Deng, Ping Yi, Jianhua Yu.
      N6-methyladenosine (m6A) is the most abundant epigenetic modification of RNA, and its dysregulation drives aberrant transcription and translation programs that promote cancer occurrence and progression. Although defective gene regulation resulting from m6A often affects oncogenic and tumor-suppressing networks, m6A can also modulate tumor immunogenicity and immune cells involved in anti-tumor responses. Understanding this counterintuitive concept can aid the design of new drugs that target m6A to potentially improve the outcomes of cancer immunotherapies. Here, we provide an up-to-date and comprehensive overview of how m6A modifications intrinsically affect immune cells and how alterations in tumor cell m6A modifications extrinsically affect immune cell responses in the tumor microenvironment (TME). We also review strategies for modulating endogenous anti-tumor immunity and discuss the challenge of reshaping the TME. Strategies include: combining specific and efficient inhibitors against m6A regulators with immune checkpoint blockers; generating an effective programmable m6A gene-editing system that enables efficient manipulation of individual m6A sites; establishing an effective m6A modification system to enhance anti-tumor immune responses in T cells or natural killer cells; and using nanoparticles that specifically target tumor-associated macrophages (TAMs) to deliver messenger RNA or small interfering RNA of m6A-related molecules that repolarize TAMs, enabling them to remodel the TME. The goal of this review is to help the field understand how m6A modifications intrinsically and extrinsically shape immune responses in the TME so that better cancer immunotherapy can be designed and developed.
    Keywords:  Cancer immunotherapy; Epigenetics; N 6-methyladenosine; Tumor microenvironment; m6A modification; m6A regulators
    DOI:  https://doi.org/10.1186/s12943-022-01558-0
  11. Cancer Res. 2022 Mar 18. pii: canres.3710.2021. [Epub ahead of print]
    Oncogenic and tumor-suppressive functions of the RNA demethylase FTO.
    Hidde R Zuidhof, Cornelis F Calkhoven.
      The epitranscriptome represents the more than 140 types of chemically varying and reversable RNA modifications affecting RNA fate. Among these, the most relevant for this review are the mRNA-modifications N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am). Epitranscriptomic mRNA biology involves RNA methyltransferases (so called "writers"), RNA demethylases ("erasers"), and RNA-binding proteins ("readers") that interact with methylation sites to determine the functional outcome of the modification. In this review, we discuss the role of a specific RNA demethylase encoded by the fat mass and obesity associated gene (FTO) in cancer. FTO initially became known as the strongest genetic link for human obesity. Only in 2010, 16 years after its discovery, was its enzymatic function as a demethylase clarified, and only recently has its role in the development of cancer been revealed. FTO functions are challenging to study and interpret because of its genome-wide effects on transcript turnover and translation. We review the discovery of FTO and its enzymatic function, the tumor-promoting and suppressive roles of FTO in selected cancer types, and its potential as a therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3710
  12. Nat Commun. 2022 Mar 18. 13(1): 1469
    WTAP-mediated m6A modification of lncRNA NORAD promotes intervertebral disc degeneration.
    Gaocai Li, Liang Ma, Shujie He, Rongjin Luo, Bingjin Wang, Weifeng Zhang, Yu Song, Zhiwei Liao, Wencan Ke, Qian Xiang, Xiaobo Feng, Xinghuo Wu, Yukun Zhang, Kun Wang, Cao Yang.
      N6-methyladenosine (m6A) is the most prevalent RNA modification at the posttranscriptional level and involved in various diseases and cellular processes. However, the underlying mechanism of m6A regulation in intervertebral disc degeneration (IVDD) remains elusive. Here, we show that methylation of the lncRNA NORAD significantly increases in senescent nucleus pulposus cells (NPCs) by m6A sequencing. Subsequent loss- and gain-of-function experiments reveal WTAP is increased in senescent NPCs due to an epigenetic increase in H3K4me3 of the promoter mediated by KDM5a, and significantly promotes NORAD m6A modification. Furthermore, YTHDF2-mediated decay of NORAD is enhanced in senescent NPCs, and then deficiency of NORAD results in less sequestraion of PUMILIO proteins, contributing to the augmented activity of PUM1/2, thus repressing the expression of target E2F3 mRNAs and promoting the cellular senescence. Here, we show interruption of NORAD m6A modification or the NORAD/PUMILIO/E2F3 axis could serve as a potential therapeutic target to inhibit the senescence of NPCs and development of IVDD.
    DOI:  https://doi.org/10.1038/s41467-022-28990-6
  13. Front Immunol. 2022 ;13 813979
    ALKBH5-Mediated m6A Modification of A20 Regulates Microglia Polarization in Diabetic Retinopathy.
    Tingting Chen, Wenhui Zhu, Congyao Wang, Xia Dong, Fenfen Yu, Yihua Su, Jingwen Huang, Lijun Huo, Pengxia Wan.
      Background: To investigate the role of microglia polarization in the pathogenesis of diabetic retinopathy, and study the mechanism of ALKBH5-mediated m6A modification of A20 of retinal microglia polarization.Methods: Diabetics rats were constructed and the M1/M2 polarization of retinal microglia was determined using immunofluorescence, flow cytometry, and quantitative real-time PCR (qRT-PCR). Glucose at different concentrations was added to treat the microglia, and the polarization rate was detected. RNA sequencing was performed to identify the differentially expressed gene in glucose treated microglia, and A20 expression was confirmed by qRT-PCR and western blotting. Lentiviruses encoding shRNA for A20 or overexpressing A20 were constructed to clarify the role of A20 in microglia polarization in vitro and vivo. N6-methyladenosine (m6A) modification level and degradation rate of A20 were determined and m6A related proteins were detected.
    Results: Diabetics rats showed a higher M1 polarization rate but lower M2 polarization rate of retinal microglia. With the increase of glucose concentration, microglia tend to polarize into M1 inflammatory type rather than M2 anti-inflammatory type. Shown by RNA sequencing, glucose treated microglia showed a differentially expressed gene profile, which was enriched in kinds of inflammatory categories and pathways. A20 expression was lower in microglia with glucose treatment, which was demonstrated to negatively regulate the M1 polarization. Moreover, intraocular injection of A20-overexpression lentiviruses (OE-A20) rectified the enhanced M1 retinal microglia polarization of diabetes rats. The higher m6A modification level and faster degradation rate of A20 was observed in glucose treated microglia, which was mediated by m6A demethylase ALKBH5.
    Conclusion: Lower expression A20 resulted in the enhanced M1 polarization of retinal microglia in diabetic retinopathy, which was caused by ALKBH5 mediated m6A modification. This study may provide new perspectives on not only the pathogenesis but also the diagnosis and treatment for diabetic retinopathy.
    Keywords:  A20; ALKBH5; diabetic retinopathy; m6A modification; microglia polarization
    DOI:  https://doi.org/10.3389/fimmu.2022.813979
  14. J Genet Genomics. 2022 Mar 15. pii: S1673-8527(22)00078-9. [Epub ahead of print]
    Loss of Wtap results in cerebellar ataxia and degeneration of Purkinje cells.
    Yeming Yang, Guo Huang, Xiaoyan Jiang, Xiao Li, Kuanxiang Sun, Yi Shi, Zhenglin Yang, Xianjun Zhu.
      N6-methyladenosine (m6A) modification, which is achieved by the METTL3/METTL14/WTAP methyltransferase complex, is the most abundant internal mRNA modification. Although recent evidence indicates that m6A can regulate neurodevelopment as well as synaptic function, the roles of m6A modification in the cerebellum and related synaptic connections are not well established. Here, we report that Purkinje cell (PC)-specific WTAP knockout mice display early-onset ataxia concomitant with cerebellar atrophy due to extensive PC degeneration and apoptotic cell death. Loss of Wtap also causes the aberrant degradation of multiple PC synapses. WTAP depletion leads to decreased expression levels of METTL3/14 and reduced m6A methylation in PCs. Moreover, the expression of GFAP and NF-L in the degenerating cerebellum is increased, suggestive of severe neuronal injuries. In conclusion, this study demonstrates the critical role of WTAP-mediated m6A modification in cerebellar PCs, thus providing unique insights related to neurodegenerative disorders.
    DOI:  https://doi.org/10.1016/j.jgg.2022.03.001
  15. J Oncol. 2022 ;2022 2910491
    Application of m6A and TME in Predicting the Prognosis and Treatment of Clear Cell Renal Cell Carcinoma.
    Dongchen Pei, Chaojie Xu, Dong Wang, Xiaoxue Shi, Yurui Zhang, Yi Liu, Nan Liu, Jianhua Guo, Yang Yu, Zhengjun Kang, Haipeng Zhu.
      Background: Previous studies have shown that RNA N6-methyladenosine (m6A) plays an important role in the construction of the tumor microenvironment (TME). However, how m6A plays a role in the TME of clear cell renal cell carcinoma remains unclear.Methods: Based on 23 m6A modulators, we applied consensus cluster analysis to explore the different m6A modification profiles of ccRCC. The CIBERSORT method was employed to reveal the correlation between TME immune cell infiltration and different m6A modification patterns. A m6A score was constructed using a principal component analysis algorithm to assess and quantify the m6A modification patterns of individual tumors.
    Results: Three distinct m6A modification patterns of ccRCC were identified. The characteristics of TME cell infiltration in these three patterns were consistent with immune rejection phenotype, immune inflammation phenotype, and immune desert phenotype. In particular, when m6A scores were high, TME was characterized by immune cell infiltration and patient survival was higher (p < 0.05). When m6A scores were low, TME was characterized by immunosuppression and patient survival was lower (p < 0.05). The immunotherapy cohort confirmed that patients with higher m6A scores had significant therapeutic advantages and clinical benefits.
    Conclusions: The m6A modification plays an important role in the formation of TME. The m6A scoring system allows the identification of m6A modification patterns in individual tumors, discriminates the immune infiltrative features of TME, and provides more effective prognostic indicators and treatment strategies for immunotherapy.
    DOI:  https://doi.org/10.1155/2022/2910491
  16. Cancer Lett. 2022 Mar 09. pii: S0304-3835(22)00090-8. [Epub ahead of print]534 215615
    Therapeutic targeting m6A-guided miR-146a-5p signaling contributes to the melittin-induced selective suppression of bladder cancer.
    Rucheng Yan, Weiwei Dai, Ruixin Wu, Houbao Huang, Minfeng Shu.
      Abnormal RNA methylation and dysregulation of miRNA are frequently occurred in bladder cancer. Melittin is a potential drug candidate for intravesical chemotherapy against bladder cancer. However, the underlying epigenetic mechanism by which melittin-induced anti-tumor effect remains unclear. Here, we showed that melittin selectively induced apoptosis of bladder cancer cells in a METTL3-dependent manner. Ectopic expression of METTL3 significantly blocked melittin-induced apoptosis in vitro and in vivo. MicroRNA-sequence analysis identified miR-146a-5p suppression contributed to the melittin-induced selective antitumor effect. Further investigation revealed that METTL3-guided m6A modification methylated pri-miR-146 at the flanking sequence, which was responsible for the pri-miR-146 maturation. Moreover, NUMB/NOTCH2 axis was identified as a downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of patients with bladder cancer. Our study indicates that METTL3 acts as a fate determinant that controls the sensitivity of bladder cancer cells to melittin treatment. Moreover, METTL3/miR-146a-5p/NUMB/NOTCH2 axis plays an oncogenic role in bladder cancer pathogenesis and could be a potential therapeutic target for recurrent bladder cancer treatment.
    Keywords:  Apoptosis; METTL3; RNA methylation; Targeting therapy
    DOI:  https://doi.org/10.1016/j.canlet.2022.215615
  17. Cell Death Dis. 2022 Mar 14. 13(3): 234
    Global profiling reveals common and distinct N6-methyladenosine (m6A) regulation of innate immune responses during bacterial and viral infections.
    Jian Feng, Teng Zhang, Océane Sorel, Wen Meng, Xinquan Zhang, Zhao Lai, Weiming Yuan, Yidong Chen, Yufei Huang, Shou-Jiang Gao.
      N6-methyladenosine (m6A) is a dynamic post-transcriptional RNA modification influencing all aspects of mRNA biology. While m6A modifications during numerous viral infections have been described, the role of m6A in innate immune response remains unclear. Here, we examined cellular m6A epitranscriptomes during infections of Pseudomonas aeruginosa and herpes simplex virus type 1 (HSV-1), and lipopolysaccharide (LPS) stimulation to identify m6A-regulated innate immune response genes. We showed that a significant portion of cellular genes including many innate immune response genes underwent m6A modifications in 5'UTR and 3'UTR. We identified common and distinct m6A-modified genes under different stimulating conditions. Significantly, the expression of a subset of innate immune response genes was positively correlated with m6A level. Importantly, we identified genes that had significant enrichments of m6A peaks during P. aeruginosa infection following knockdown of m6A "eraser" ALKBH5, confirming the regulation of these genes by m6A and ALKBH5. Among them, we confirmed the association of m6A modification with gene expression in immune response genes TNFAIP3, IFIT1, IFIT2 and IFIH1. Taken together, our results revealed the vital role of m6A in regulating innate immunity against bacterial and viral infections. These works also provided rich resources for the scientific community.
    DOI:  https://doi.org/10.1038/s41419-022-04681-4
  18. Front Oncol. 2022 ;12 844613
    Comprehensive Analysis of the Transcriptome-Wide m6A Methylome in Endometrioid Ovarian Cancer.
    Li Yang, Xin Chen, Xiang Qian, Jiejie Zhang, Meijuan Wu, Aijun Yu.
      Emerging studies have revealed that N6-methyladenosine modification is involved in the development of various cancers. However, the m6A modification pattern of endometrioid ovarian cancer (EOC) has not been demonstrated. In the present study, high-throughput sequencing combined with methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing were used to obtain the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time. The roles of methyltransferase-like 3 (METTL3) in EOC cell line COV362 were explored. In total, 39,237 m6A-modified peaks related to 17,082 genes were identified in the EOC group, and 52,848 m6A peaks representing 19,349 genes were detected in endometriosis group. Functional enrichment analysis revealed that m6A enriched genes were associated with tight junctions, cell adhesion molecules, platinum drug resistance, adherens junction, and more. METTL3 knockdown in the COV362 cells significantly decreased cell proliferation, promoted cell apoptosis, and induced cell cycle arrest at the G0/G1 phase. Our study presented the transcriptome-wide m6A modifications of endometrioid ovarian cancer for the first time and revealed various differentially expressed genes with methylated m6A modifications. This study may provide new directions for in-depth research of the underlying molecular mechanisms and signaling pathways of EOC development and progression.
    Keywords:  METTL3; MeRIP-seq; N6-methyladenosine; endometrioid ovarian cancer; modification patterns
    DOI:  https://doi.org/10.3389/fonc.2022.844613
  19. J Bioinform Comput Biol. 2022 Mar 14. 2250004
    RNA modification writers influence tumor microenvironment in gastric cancer and prospects of targeted drug therapy.
    Peng Song, Sheng Zhou, Xiaoyang Qi, Yuwen Jiao, Yu Gong, Jie Zhao, Haojun Yang, Zhifen Qian, Jun Qian, Liming Tang.
      Background: RNA adenosine modifications are crucial for regulating RNA levels. N6-methyladenosine (m6A), N1-methyladenosine (m1A), adenosine-to-inosine RNA editing, and alternative polyadenylation (APA) are four major RNA modification types. Methods: We evaluated the altered mRNA expression profiles of 27 RNA modification enzymes and compared the differences in tumor microenvironment (TME) and clinical prognosis between two RNA modification patterns using unsupervised clustering. Then, we constructed a scoring system, WM_score, and quantified the RNA modifications in patients of gastric cancer (GC), associating WM_score with TME, clinical outcomes, and effectiveness of targeted therapies. Results: RNA adenosine modifications strongly correlated with TME and could predict the degree of TME cell infiltration, genetic variation, and clinical prognosis. Two modification patterns were identified according to high and low WM_scores. Tumors in the WM_score-high subgroup were closely linked with survival advantage, CD4[Formula: see text] T-cell infiltration, high tumor mutation burden, and cell cycle signaling pathways, whereas those in the WM_score-low subgroup showed strong infiltration of inflammatory cells and poor survival. Regarding the immunotherapy response, a high WM_score showed a significant correlation with PD-L1 expression, predicting the effect of PD-L1 blockade therapy. Conclusion: The WM_scoring system could facilitate scoring and prediction of GC prognosis.
    Keywords:  Gastric cancer; RNA modification “writer”; WM_score; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1142/S0219720022500044
  20. Nat Commun. 2022 Mar 18. 13(1): 1478
    N7-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis.
    Hui Han, Chunlong Yang, Jieyi Ma, Shuishen Zhang, Siyi Zheng, Rongsong Ling, Kaiyu Sun, Siyao Guo, Boxuan Huang, Yu Liang, Lu Wang, Shuang Chen, Zhaoyu Wang, Wei Wei, Ying Huang, Hao Peng, Yi-Zhou Jiang, Junho Choe, Shuibin Lin.
      Mis-regulated RNA modifications promote the processing and translation of oncogenic mRNAs to facilitate cancer progression, while the molecular mechanisms remain unclear. Here we reveal that tRNA m7G methyltransferase complex proteins METTL1 and WDR4 are significantly up-regulated in esophageal squamous cell carcinoma (ESCC) tissues and associated with poor ESCC prognosis. In addition, METTL1 and WDR4 promote ESCC progression via the tRNA m7G methyltransferase activity in vitro and in vivo. Mechanistically, METTL1 or WDR4 knockdown leads to decreased expression of m7G-modified tRNAs and reduces the translation of a subset of oncogenic transcripts enriched in RPTOR/ULK1/autophagy pathway. Furthermore, ESCC models using Mettl1 conditional knockout and knockin mice uncover the essential function of METTL1 in promoting ESCC tumorigenesis in vivo. Our study demonstrates the important oncogenic function of mis-regulated tRNA m7G modification in ESCC, and suggest that targeting METTL1 and its downstream signaling axis could be a promising therapeutic target for ESCC treatment.
    DOI:  https://doi.org/10.1038/s41467-022-29125-7
  21. Ann Transl Med. 2022 Jan;10(2): 83
    YTHDF3 facilitates triple-negative breast cancer progression and metastasis by stabilizing ZEB1 mRNA in an m6A-dependent manner.
    Yuxiang Lin, Xuan Jin, Qian Nie, Minyan Chen, Wenhui Guo, Lili Chen, Yan Li, Xiaobin Chen, Wenzhe Zhang, Hanxi Chen, Meichen Jiang, Han Xiao, Jie Zhang, Fangmeng Fu, Chuan Wang.
      Background: The YTH domain family protein 3 (YTHDF3) is an important N6-methyladenosine (m6A) reader which is involved in multiple cancers. However, the biological role and mechanisms of action for YTHDF3 in triple-negative breast cancer (TNBC) remains to be elucidated.Methods: The expression of YTHDF3 in TNBC tissues was evaluated using The Cancer Genome Atlas (TCGA) database, BC-GenExMiner, and immunohistochemistry (IHC) staining. Cell migration, invasion, and epithelial-mesenchymal transition (EMT) were validated by wound healing assays, transwell assays, and Western blot (WB) analyses. The association between YTHDF3 and zinc finger E-box-binding homeobox 1 (ZEB1) was confirmed by Pearson correlation analysis. RNA-binding protein immunoprecipitation (RIP) assays and mRNA actinomycin stability analyses were applied to confirm whether YTHDF3 could interact with ZEB1in an m6A-dependent manner.
    Results: The expression of YTHDF3 was correlated with poorer disease-free survival (DFS) and overall survival (OS) in TNBC patients. Functional experiments indicated that YTHDF3 positively regulated cell migration, invasion, and EMT in TNBC cells. Moreover, ZEB1 was identified as a key downstream target for YTHDF3 and YTHDF3 could enhance ZEB1 mRNA stability in an m6A-dependent manner. Inhibition of YTHDF3 reduced migration, invasion, and EMT, all of which were reversed by rescue experiments overexpressing ZEB1.
    Conclusions: The findings herein confirmed that the YTHDF3/ZEB1 axis plays an important role in the progression and metastasis of TNBC. YTHDF3 is a promising prognosis biomarker and potential therapeutic target for patients with TNBC.
    Keywords:  Triple-negative breast cancer (TNBC); YTH domain family 3 (YTHDF3); epithelial-mesenchymal transition (EMT); metastasis; zinc finger E-box-binding homeobox 1 (ZEB1)
    DOI:  https://doi.org/10.21037/atm-21-6857
  22. Hereditas. 2022 Mar 18. 159(1): 17
    N6-methyladenosine-related lncRNAs is a potential marker for predicting prognosis and immunotherapy in ovarian cancer.
    Xin Nie, Jichun Tan.
      BACKGROUND: With a lack of specific symptoms, ovarian cancer (OV) is often diagnosed at an advanced stage. This coupled with inadequate prognostic indicators and treatments with limited therapeutic effect make OV the deadliest type of gynecological tumor. Recent research indicates that N6-methyladenosine (m6A) and long-chain non-coding RNA (lncRNA) play important roles in the prognosis of OV and the efficacy of immunotherapy.RESULTS: Using the Cancer Genome Atlas (TCGA) OV-related data set and the expression profiles of 21 m6A-related genes, we identified two m6A subtypes, and the differentially expressed genes between the two. Based on the differentially expressed lncRNAs in the two m6A subtypes and the lncRNAs co-expressed with the 21 m6A-related genes, single-factor cox and LASSO regression were used to further isolate the 13 major lncRNAs. Finally, multi-factor cox regression was used to construct a m6A-related lncRNA risk score model for OV, with good performance in patient prognosis. Using risk score, OV tumor samples are divided into with high- and low-score groups. We explored the differences in clinical characteristics, tumor mutational burden, and tumor immune cell infiltration between the two groups, and evaluated the risk score's ability to predict the benefit of immunotherapy.
    CONCLUSION: Our m6A-based lncRNA risk model could be used to predict the prognosis and immunotherapy response of future OV patients.
    Keywords:  Immunotherapy; Ovarian cancer; Prognostic signatures; lncRNA; m6A
    DOI:  https://doi.org/10.1186/s41065-022-00222-3
  23. Wiley Interdiscip Rev RNA. 2022 Mar 17. e1725
    The regulatory role of N6 -methyladenosine modification in the interaction between host and microbes.
    Ruhao Zhuo, Menghui Xu, Xiaoyun Wang, Bin Zhou, Xin Wu, Vanessa Leone, Eugene B Chang, Xiang Zhong.
      N6 -methyladenosine (m6 A) is the most prevalent posttranscriptional modification in eukaryotic mRNAs. Dynamic and reversible m6 A modification regulates gene expression to control cellular processes and diverse biological functions. Growing evidence indicated that m6 A modification is involved in the homeostasis of host and microbes (mostly viruses and bacteria). Disturbance of m6 A modification affects the life cycles of viruses and bacteria, however, these microbes could in turn change host m6 A modification leading to human disease including autoimmune diseases and cancer. Thus, we raise the concept that m6 A could be a "messenger" molecule to participate in the interactions between host and microbes. In this review, we summarize the regulatory mechanisms of m6 A modification on viruses and commensal microbiota, highlight the roles of m6 A methylation in the interaction of host and microbes, and finally discuss drugs development targeting m6 A modification. This article is categorized under: RNA in Disease and Development > RNA in Disease.
    Keywords:  M6A modification; crosstalk; host; microbiota; virus
    DOI:  https://doi.org/10.1002/wrna.1725
  24. Mol Ther. 2022 Mar 09. pii: S1525-0016(22)00160-5. [Epub ahead of print]
    PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer.
    Ying Wu, Zhe Wang, Lu Han, Zhihao Guo, Bohua Yan, Lili Guo, Huadong Zhao, Mengying Wei, Niuniu Hou, Jing Ye, Zhe Wang, Changhong Shi, Suling Liu, Ceshi Chen, Suning Chen, Ting Wang, Jun Yi, JianPing Zhou, Libo Yao, Wenxia Zhou, Rui Ling, Jian Zhang.
      Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB Homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy that targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.
    DOI:  https://doi.org/10.1016/j.ymthe.2022.03.003
  25. Front Cardiovasc Med. 2022 ;9 852775
    Loss of m6A Methyltransferase METTL5 Promotes Cardiac Hypertrophy Through Epitranscriptomic Control of SUZ12 Expression.
    Yanchuang Han, Tailai Du, Siyao Guo, Lu Wang, Gang Dai, Tianxin Long, Ting Xu, Xiaodong Zhuang, Chen Liu, Shujuan Li, Dihua Zhang, Xinxue Liao, Yugang Dong, Kathy O Lui, Xu Tan, Shuibin Lin, Yili Chen, Zhan-Peng Huang.
      Enhancement of protein synthesis from mRNA translation is one of the key steps supporting cardiomyocyte hypertrophy during cardiac remodeling. The methyltransferase-like5 (METTL5), which catalyzes m6A modification of 18S rRNA at position A1832, has been shown to regulate the efficiency of mRNA translation during the differentiation of ES cells and the growth of cancer cells. It remains unknown whether and how METTL5 regulates cardiac hypertrophy. In this study, we have generated a mouse model, METTL5-cKO, with cardiac-specific depletion of METTL5 in vivo. Loss function of METTL5 promotes pressure overload-induced cardiomyocyte hypertrophy and adverse remodeling. The regulatory function of METTL5 in hypertrophic growth of cardiomyocytes was further confirmed with both gain- and loss-of-function approaches in primary cardiomyocytes. Mechanically, METTL5 can modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptomic shift during cardiac hypertrophy. Altogether, our study may uncover an important translational regulator of cardiac hypertrophy through m6A modification.
    Keywords:  METTL5; RNA modification; SUZ12; cardiac hypertrophy; translational regulation
    DOI:  https://doi.org/10.3389/fcvm.2022.852775
  26. Front Oncol. 2022 ;12 786266
    Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.
    Lingfang Wang, Jian Zhang, Yingfeng Su, Yasen Maimaitiyiming, Siqi Yang, Zhangjin Shen, Shitong Lin, Shizhen Shen, Guankai Zhan, Fenfen Wang, Chih-Hung Hsu, Xiaodong Cheng.
      RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women's reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.
    Keywords:  KRT13; NSUN2; YBX1; cervical cancer; endometrial cancer; m5C; ovarian cancer
    DOI:  https://doi.org/10.3389/fonc.2022.786266
  27. Epigenomics. 2022 Mar 14.
    Advanced glycation end products alter the m6A-modified RNA profiles in human dermal fibroblasts.
    Mengting Ouyang, Jiaqi Fang, Mengyao Wang, Xianyin Huang, Jingjing Lan, Yingying Qu, Wei Lai, Qingfang Xu.
      Background: To explore advanced glycation end products (AGEs)-induced m6A modification in fibroblasts and its potential role in photoaging. Methods: We studied m6A modification in AGEs-bovine serum albumin-treated fibroblasts with m6A-mRNA & lncRNA epitranscriptomic microarray and bioinformatics analysis. The m6A modification level was also investigated in skin samples. Results: m6A methylation microarray analysis revealed m6A modification profiles in AGEs-treated fibroblasts. Gene ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interaction and competing endogenous RNA network analysis indicated that the genes of differentially methylated mRNAs and lncRNAs were mainly related to inflammation processes. We also found that AGEs-bovine serum albumin dose-dependently increased the m6A level and METTL14 expression in both fibroblasts and sun-exposed skin. Conclusion: Our study provided novel information regarding alterations of m6A modifications in AGEs-induced dermal fibroblasts and potential targets for treatment of photoaging.
    Keywords:  advanced glycation end products; bioinformatics analysis; fibroblasts; lncRNA; m6A methylation; photoaging; skin
    DOI:  https://doi.org/10.2217/epi-2022-0016
  28. Methods Mol Biol. 2022 ;2444 125-140
    Use of High-Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS) to Quantify Modified Nucleosides.
    Rebecca Rodell, Ning Tsao, Adit Ganguly, Nima Mosammaparast.
      Physiological and chemically induced modifications to nucleosides are common in both DNA and RNA. Physiological forms of these modifications play critical roles in gene expression, yet aberrant marks, if left unrepaired, may be associated with increased genome instability. Due to the low prevalence of these marks in most samples of interest, a highly sensitive method is needed for their detection and quantitation. High-performance liquid chromatography, coupled to mass spectrometry (HPLC-MS), provides this high degree of sensitivity while also being adaptable to nearly any modified nucleoside of interest and still maintaining exquisite specificity. In this chapter, we demonstrate how to use HPLC-MS to analyze the catalytic activity of a nucleic acid demethylase, to quantify the prevalence of N6-methyladenosine from RNA, and to determine the kinetics of alkylation damage repair.
    Keywords:  AlkB; Epitranscriptomics; Mass spectrometry; Methylation; Nucleoside
    DOI:  https://doi.org/10.1007/978-1-0716-2063-2_8
  29. Lipids Health Dis. 2022 Mar 13. 21(1): 29
    Fat mass and obesity-associated protein promotes liver steatosis by targeting PPARα.
    Xiaohui Wei, Jielei Zhang, Min Tang, Xuejiao Wang, Nengguang Fan, Yongde Peng.
      BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. The fat mass and obesity-associated protein (FTO) has been shown to be involved in obesity; however, its role in NAFLD and the underlying molecular mechanisms remain largely unknown.METHODS: FTO expression was first examined in the livers of patients with NAFLD and animal and cellular models of NAFLD by real-time PCR and Western blotting. Next, its role in lipid accumulation in hepatocytes was assessed both in vitro and in vivo via gene overexpression and knockdown studies.
    RESULTS: FTO expression was obviously elevated in the livers of mice and humans with hepatic steatosis, probably due to its decreased ubiquitination. FTO overexpression in HepG2 cells induced triglyceride accumulation, whereas FTO knockdown exerted an opposing effect. Consistent with the findings of in vitro studies, adeno-associated viruses 8 (AAV8)-mediated FTO overexpression in the liver promoted hepatic steatosis in C57BL/6J mice. Mechanistically, FTO inhibited the mRNA of peroxisome proliferator-activated receptor α (PPARα) in hepatocytes. Activation of PPARα by its agonist GW7647 reversed lipid accumulation in hepatocytes induced by FTO overexpression.
    CONCLUSIONS: Overall, FTO expression is increased in NAFLD, and it promotes hepatic steatosis by targeting PPARα.
    Keywords:  Fat and obesity associated protein; Nonalcoholic fatty liver disease; Peroxisome proliferator-activated receptor α
    DOI:  https://doi.org/10.1186/s12944-022-01640-y
  30. Bioengineered. 2022 Mar 14.
    PolyC-RNA-binding protein 1 (PCBP1) enhances tropomyosin 3 (TPM3) mRNA stability to promote the progression of esophageal squamous cell carcinoma.
    Kaiming Peng, Xiaoqiang Chen, Anqin Lin, Zhangwei Tong, Wenwei Lin.
      The molecular etiology of esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Understanding of the molecular mechanisms and finding new therapeutic targets for ESCC is of crucial importance. PolyC-RNA-binding protein 1 (PCBP1) is an RNA-binding protein. Here, we found overexpressed PCBP1 in esophageal cancer tissues by quantitative polymerase chain reaction (qPCR) and western blotting analysis. PCBP1 knockdown significantly attenuated migratory and invasion abilities of ESCC cells. Mechanistically, PCBP1 bound directly to Tropomyosin 3 (TPM3) mRNA that was verified by RNA-protein immunoprecipitation (RIP) assay. PCBP1 knockdown markedly reduced messenger RNA (mRNA) levels of TPM3. After inhibiting intracellular mRNA synthesis with actinomycin D (ActD), it was found that PCBP1 knockdown contributed to a significant decrease in TPM3 mRNA degradation. Furthermore, PCBP1 promoted migration and invasion of EC cells by directly binding to the 3'UTR of TPM3 mRNA, increasing TPM3 mRNA stability. Taken together, PCBP1 acting as a pro-oncogenic factor enhances TPM3 mRNA stability by directly binding to the 3'UTR of TPM3 mRNA in esophageal squamous cell carcinoma. Our findings provide a new perspective for understanding the molecular mechanism of esophageal carcinogenesis, and PCBP1 is a promising therapeutic target.
    Keywords:  PCBP1; TPM3; esophageal squamous cell carcinoma (ESCC); mRNA stability
    DOI:  https://doi.org/10.1080/21655979.2022.2053801
  31. Cancer Res. 2022 Mar 18. pii: canres.2106.2021. [Epub ahead of print]
    M6A RNA Methylation Regulates Histone Ubiquitination to Support Cancer Growth and Progression.
    Pooja Yadav, Panneerdoss Subbarayalu, Daisy Medina, Saif Nirzhor, Santosh Timilsina, Subapriya Rajamanickam, Vijay K Eedunuri, Yogesh Gupta, Siyuan Zheng, Nourhan Abdelfattah, Yufei Huang, Ratna Vadlamudi, Robert Hromas, Paul Meltzer, Peter Houghton, Yidong Chen, Manjeet K Rao.
      Osteosarcoma is the most common malignancy of the bone, yet the survival for osteosarcoma patients is virtually unchanged over the past 30 years. This is principally because development of new therapies is hampered by a lack of recurrent mutations that can be targeted in osteosarcoma. Here, we report that epigenetic changes via mRNA methylation holds great promise to better understand the mechanisms of osteosarcoma growth and to develop targeted therapeutics. In osteosarcoma patients, the RNA demethylase ALKBH5 was amplified and higher expression correlated with copy number changes. ALKBH5 was critical for promoting osteosarcoma growth and metastasis, yet it was dispensable for normal cell survival. Me-RIP-seq analysis and functional studies showed that ALKBH5 mediates its pro-tumorigenic function by regulating m6A levels of histone deubiquitinase USP22 and the ubiquitin ligase RNF40. ALKBH5-mediated m6A deficiency in osteosarcoma led to increased expression of USP22 and RNF40 that resulted in inhibition of histone H2A monoubiquitination and induction of key pro-tumorigenic genes, consequently driving unchecked cell cycle progression, incessant replication and DNA repair. RNF40, which is historically known to ubiquitinate H2B, inhibited H2A ubiquitination in cancer by interacting with and affecting the stability of DDB1-CUL4-based ubiquitin E3 ligase complex. Taken together, this study directly links increased activity of ALKBH5 with dysregulation of USP22/RNF40 and histone ubiquitination in cancers. More broadly, these results suggest that m6A RNA methylation works in concert with other epigenetic mechanisms to control cancer growth.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2106
  32. Nat Chem Biol. 2022 Mar 17.
    Structure and mechanism of the methyltransferase ribozyme MTR1.
    Carolin P M Scheitl, Mateusz Mieczkowski, Hermann Schindelin, Claudia Höbartner.
      RNA-catalyzed RNA methylation was recently shown to be part of the catalytic repertoire of ribozymes. The methyltransferase ribozyme MTR1 catalyzes the site-specific synthesis of 1-methyladenosine (m1A) in RNA, using O6-methylguanine (m6G) as a methyl group donor. Here, we report the crystal structure of MTR1 at a resolution of 2.8 Å, which reveals a guanine-binding site reminiscent of natural guanine riboswitches. The structure represents the postcatalytic state of a split ribozyme in complex with the m1A-containing RNA product and the demethylated cofactor guanine. The structural data suggest the mechanistic involvement of a protonated cytidine in the methyl transfer reaction. A synergistic effect of two 2'-O-methylated ribose residues in the active site results in accelerated methyl group transfer. Supported by these results, it seems plausible that modified nucleotides may have enhanced early RNA catalysis and that metabolite-binding riboswitches may resemble inactivated ribozymes that have lost their catalytic activity during evolution.
    DOI:  https://doi.org/10.1038/s41589-022-00976-x
  33. Mol Cancer. 2022 Mar 12. 21(1): 74
    Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression.
    Hao Liu, Danxiu Li, Lina Sun, Hongqiang Qin, Ahui Fan, Lingnan Meng, Ramona Graves-Deal, Sarah E Glass, Jeffrey L Franklin, Qi Liu, Jing Wang, Timothy J Yeatman, Hao Guo, Hong Zong, Shuilin Jin, Zhiyu Chen, Ting Deng, Ying Fang, Cunxi Li, John Karijolich, James G Patton, Xin Wang, Yongzhan Nie, Daiming Fan, Robert J Coffey, Xiaodi Zhao, Yuanyuan Lu.
      BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a process linked to metastasis and drug resistance with non-coding RNAs (ncRNAs) playing pivotal roles. We previously showed that miR-100 and miR-125b, embedded within the third intron of the ncRNA host gene MIR100HG, confer resistance to cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, in colorectal cancer (CRC). However, whether the MIR100HG transcript itself has a role in cetuximab resistance or EMT is unknown.METHODS: The correlation between MIR100HG and EMT was analyzed by curating public CRC data repositories. The biological roles of MIR100HG in EMT, metastasis and cetuximab resistance in CRC were determined both in vitro and in vivo. The expression patterns of MIR100HG, hnRNPA2B1 and TCF7L2 in CRC specimens from patients who progressed on cetuximab and patients with metastatic disease were analyzed by RNAscope and immunohistochemical staining.
    RESULTS: The expression of MIR100HG was strongly correlated with EMT markers and acted as a positive regulator of EMT. MIR100HG sustained cetuximab resistance and facilitated invasion and metastasis in CRC cells both in vitro and in vivo. hnRNPA2B1 was identified as a binding partner of MIR100HG. Mechanistically, MIR100HG maintained mRNA stability of TCF7L2, a major transcriptional coactivator of the Wnt/β-catenin signaling, by interacting with hnRNPA2B1. hnRNPA2B1 recognized the N6-methyladenosine (m6A) site of TCF7L2 mRNA in the presence of MIR100HG. TCF7L2, in turn, activated MIR100HG transcription, forming a feed forward regulatory loop. The MIR100HG/hnRNPA2B1/TCF7L2 axis was augmented in specimens from CRC patients who either developed local or distant metastasis or had disease progression that was associated with cetuximab resistance.
    CONCLUSIONS: MIR100HG and hnRNPA2B1 interact to control the transcriptional activity of Wnt signaling in CRC via regulation of TCF7L2 mRNA stability. Our findings identified MIR100HG as a potent EMT inducer in CRC that may contribute to cetuximab resistance and metastasis by activation of a MIR100HG/hnRNPA2B1/TCF7L2 feedback loop.
    Keywords:  CRC; Cetuximab resistance; EMT; MIR100HG; Metastasis; N6-methyladenosine (m6A); TCF7L2; Wnt/β-catenin signaling; hnRNPA2B1
    DOI:  https://doi.org/10.1186/s12943-022-01555-3
  34. Front Oncol. 2022 ;12 821958
    Transcriptional Expressions of ALDH1A1/B1 as Independent Indicators for the Survival of Thyroid Cancer Patients.
    Ying Cui, Yao Liu, Lan Mu, Yang Li, Gang Wu.
      Background: Aldehyde dehydrogenase (ALDH) 1 is an important enzyme involved in the regulation of several cellular mechanisms via aldehyde detoxification. High ALDH1 levels were correlated with tumorigenesis and stemness maintenance in cancer.Methods: We used UALCAN, Human Protein Atlas, Kaplan-Meier plotter, TISIDB, TIMER, and KOBAS databases to investigate the expression and role of ALDH1 in thyroid cancer progression. In addition, quantitative real-time polymerase chain reaction was performed to detect the expression of the target genes in thyroid cancer cell lines and cancer tissues.
    Results: Expression of ALDH1A1/B1 was significantly decreased based on individual cancer stages and tumor histology, and high levels of ALDH1A1/B1 were associated with poor overall survival in thyroid cancer patients. Moreover, ALDH1A1/B1 expression was negatively correlated with immune-stimulating genes, major histocompatibility complex, chemokines, and receptors.
    Conclusions: These results suggest that ALDH1A1/B1 might serve as potential prognostic biomarkers for thyroid cancer diagnosis.
    Keywords:  ALDH1; cancer progression; prognostic biomarker; thyroid cancer; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fonc.2022.821958
  35. Front Oncol. 2022 ;12 854773
    An Overview of Epigenetic Methylation in Pancreatic Cancer Progression.
    Yuhao Zhao, Mao Yang, Shijia Wang, Sk Jahir Abbas, Junzhe Zhang, Yongsheng Li, Rong Shao, Yingbin Liu.
      Over the past decades, the aberrant epigenetic modification, apart from genetic alteration, has emerged as dispensable events mediating the transformation of pancreatic cancer (PC). However, the understanding of molecular mechanisms of methylation modifications, the most abundant epigenetic modifications, remains superficial. In this review, we focused on the mechanistic insights of DNA, histone, and RNA methylation that regulate the progression of PC. The methylation regulators including writer, eraser and reader participate in the modification of gene expression associated with cell proliferation, invasion and apoptosis. Some of recent clinical trials on methylation drug targeting were also discussed. Understanding the novel regulatory mechanisms in the methylation modification may offer alternative opportunities to improve therapeutic efficacy to fight against this dismal disease.
    Keywords:  DNA methylation; Epigenetics; Histone methylation; Pancreatic cancer; RNA methylation
    DOI:  https://doi.org/10.3389/fonc.2022.854773
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