Research Advances in the Roles of N6-Methyladenosine Modification in Ovarian Cancer

Ovarian cancer (OC) is the most lethal gynecological tumor, characterized by its insidious and frequently recurring metastatic progression. Owing to limited early screening methods, over 70% of OC cases are diagnosed at advanced stages, typically stage III or IV. Recently, N6-methyladenosine (m6A) modification has emerged as a hotspot of epigenetic research, representing a significant endogenous RNA modification in higher eukaryotes. Numerous studies have reported that m6A-related regulatory factors play pivotal roles in tumor development through diverse mechanisms. Moreover, recent studies have indicated the aberrant expression of multiple regulatory factors in OC. Therefore, this paper comprehensively reviews research advancements concerning m6A in OC, aiming to elucidate the regulatory mechanism of m6A-associated regulators on pivotal aspects, such as proliferation, invasion, metastasis, and drug resistance, in OC. Furthermore, it discusses the potential of m6A-associated regulators as early diagnostic markers and therapeutic targets, thus contributing to the diagnosis and treatment of OC.

[1]  Han Li,et al.  N6-methyladenosine-modified VGLL1 promotes ovarian cancer metastasis through high-mobility group AT-hook 1/Wnt/β-catenin signaling , 2024, iScience.

[2]  Shenghan Lou,et al.  m6A methylation-mediated regulation of LncRNA MEG3 suppresses ovarian cancer progression through miR-885-5p and the VASH1 pathway , 2024, Journal of translational medicine.

[3]  Han Li,et al.  N6-methyladenosine-modified circPLPP4 sustains cisplatin resistance in ovarian cancer cells via PIK3R1 upregulation , 2024, Molecular cancer.

[4]  Yinglian Pan,et al.  BIRC5 facilitates cisplatin‐chemoresistance in a m6A‐dependent manner in ovarian cancer , 2023, Cancer medicine.

[5]  Li Lin,et al.  m6A-modified RIPK4 facilitates proliferation and cisplatin resistance in epithelial ovarian cancer. , 2023, Gynecologic oncology.

[6]  Mengjiao Zhou,et al.  Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin , 2023, Journal of Translational Medicine.

[7]  Xiang Wu,et al.  Phenethyl isothiocyanate inhibits metastasis potential of non-small cell lung cancer cells through FTO mediated TLE1 m^6A modification , 2023, Acta pharmacologica Sinica.

[8]  Min Su,et al.  N6-methyladenosine methyltransferase KIAA1429 promoted ovarian cancer aerobic glycolysis and progression through enhancing ENO1 expression , 2023, Biology Direct.

[9]  M. Xi,et al.  m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647. , 2023, International immunopharmacology.

[10]  Hong Wei,et al.  A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance , 2023, Journal of Ovarian Research.

[11]  Chunfeng Liu,et al.  c-MYC/METTL3/LINC01006 positive feedback loop promotes migration, invasion and proliferation of non-small cell lung cancer. , 2023, Biomedical journal.

[12]  T. Shi,et al.  m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway , 2023, Journal of experimental & clinical cancer research : CR.

[13]  Haishan Lin,et al.  METTL14-mediated RNA methylation in digestive system tumors , 2023, International journal of molecular medicine.

[14]  Z. Ling,et al.  Methyltransferase-like proteins in cancer biology and potential therapeutic targeting , 2023, Journal of Hematology & Oncology.

[15]  N. Wong,et al.  METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy , 2023, Cell reports. Medicine.

[16]  D. Lin,et al.  Roles and implications of mRNA N6 ‐methyladenosine in cancer , 2023, Cancer communications.

[17]  W. Kang,et al.  Targeting m6A binding protein YTHDFs for cancer therapy. , 2023, Bioorganic & medicinal chemistry.

[18]  Huifang M. Zhang,et al.  m6A reader proteins: the executive factors in modulating viral replication and host immune response , 2023, Frontiers in Cellular and Infection Microbiology.

[19]  Jiajie Luan,et al.  The emerging importance role of m6A modification in liver disease. , 2023, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[20]  A. Jemal,et al.  Colorectal cancer statistics, 2023 , 2023, CA: a cancer journal for clinicians.

[21]  Jie-Li Hu,et al.  O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner , 2023, Signal Transduction and Targeted Therapy.

[22]  Xiuzhao Fan,et al.  scm6A-seq reveals single-cell landscapes of the dynamic m6A during oocyte maturation and early embryonic development , 2023, Nature Communications.

[23]  D. Matei,et al.  N6-Methyladenosine RNA Modifications Regulate the Response to Platinum through Nicotinamide N-methyltransferase. , 2023, Molecular cancer therapeutics.

[24]  Guodong Sun,et al.  ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer , 2023, Theranostics.

[25]  A. Jemal,et al.  Cancer statistics, 2023 , 2023, CA: a cancer journal for clinicians.

[26]  P. Jin,et al.  FMRP phosphorylation modulates neuronal translation through YTHDF1 , 2022, bioRxiv.

[27]  Shoubin Cui METTL3‐mediated m6A modification of lnc RNA RHPN1‐AS1 enhances cisplatin resistance in ovarian cancer by activating PI3K/AKT pathway , 2022, Journal of clinical laboratory analysis.

[28]  Xiaoxia Zhou,et al.  FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2 , 2022, Cancers.

[29]  Zehua Wang,et al.  Identification of miR‐30c‐5p as a tumor suppressor by targeting the m6A reader HNRNPA2B1 in ovarian cancer , 2022, Cancer medicine.

[30]  M. Zhang,et al.  METTL3-mediated N6-methyladenosine modification and HDAC5/YY1 promote IFFO1 downregulation in tumor development and chemo-resistance. , 2022, Cancer letters.

[31]  M. Wei,et al.  The m6A reader IGF2BP2 regulates glutamine metabolism and represents a therapeutic target in acute myeloid leukemia. , 2022, Cancer cell.

[32]  Chunxi Wang,et al.  Cyclodextrin-Functionalized Gold Nanorods Loaded with Meclofenamic Acid for Improving N6-Methyladenosine-Mediated Second Near-Infrared Photothermal Immunotherapy. , 2022, ACS applied materials & interfaces.

[33]  Weihua Hu,et al.  Gene signature of m6A-related targets to predict prognosis and immunotherapy response in ovarian cancer , 2022, Journal of Cancer Research and Clinical Oncology.

[34]  Bo Li,et al.  Nanodrug enhances post-ablation immunotherapy of hepatocellular carcinoma via promoting dendritic cell maturation and antigen presentation , 2022, Bioactive materials.

[35]  L. Shang,et al.  Role of m6A writers, erasers and readers in cancer , 2022, Experimental Hematology & Oncology.

[36]  S. Guil,et al.  The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer. , 2022, Seminars in cancer biology.

[37]  Fang Wang,et al.  Inhibition of METTL3 attenuates renal injury and inflammation by alleviating TAB3 m6A modifications via IGF2BP2-dependent mechanisms , 2022, Science Translational Medicine.

[38]  Shuibin Lin,et al.  N6-methyladenosine (m6A) RNA modification in tumor immunity , 2022, Cancer biology & medicine.

[39]  Yongmei Zhao,et al.  Downregulation of Methyltransferase-Like 14 Promotes Ovarian Cancer Cell Proliferation Through Stabilizing TROAP mRNA , 2022, Frontiers in Oncology.

[40]  D. Yao,et al.  [Expression of METTL14 in epithelial ovarian cancer and the effect on cell proliferation, invasion and migration of A2780 and SKOV3 cells]. , 2022, Zhonghua fu chan ke za zhi.

[41]  Zhigao Chen,et al.  Long noncoding RNA UBA6-AS1 inhibits the malignancy of ovarian cancer cells via suppressing the decay of UBA6 mRNA , 2021, Bioengineered.

[42]  Li Yang,et al.  A Risk Score Model Incorporating Three m6A RNA Methylation Regulators and a Related Network of miRNAs-m6A Regulators-m6A Target Genes to Predict the Prognosis of Patients With Ovarian Cancer , 2021, Frontiers in Cell and Developmental Biology.

[43]  Lijuan Wang,et al.  METTL3 promotes the initiation and metastasis of ovarian cancer by inhibiting CCNG2 expression via promoting the maturation of pri-microRNA-1246 , 2021, Cell death discovery.

[44]  Yonghong Luo,et al.  HIF-1α Regulated WTAP Overexpression Promoting the Warburg Effect of Ovarian Cancer by m6A-Dependent Manner , 2021, Journal of immunology research.

[45]  Andrew J. Bannister,et al.  Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia , 2021, Nature.

[46]  Yue Huang,et al.  Tumors exploit FTO-mediated regulation of glycolytic metabolism to evade immune surveillance. , 2021, Cell metabolism.

[47]  Guodong Sun,et al.  ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer , 2021, Journal of experimental & clinical cancer research : CR.

[48]  Shanshan Wang,et al.  FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2 , 2021, Molecular cancer.

[49]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[50]  Jianguo Hu,et al.  CircRAB11FIP1 promoted autophagy flux of ovarian cancer through DSC1 and miR-129 , 2021, Cell Death & Disease.

[51]  T. Rana,et al.  m6A-RNA Demethylase FTO Inhibitors Impair Self-Renewal in Glioblastoma Stem Cells , 2021, ACS chemical biology.

[52]  Y. Liu,et al.  The methylation modification of m6A regulators contributes to the prognosis of ovarian cancer , 2021, Annals of translational medicine.

[53]  Jinhui Liu,et al.  m6A RNA methylation regulators were associated with the malignancy and prognosis of ovarian cancer , 2021, Bioengineered.

[54]  Jing Zhang,et al.  Clinicopathological and immunological characterization of RNA m6A methylation regulators in ovarian cancer , 2020, Molecular genetics & genomic medicine.

[55]  Bao-qin Liu,et al.  m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells. , 2020, Biochimica et biophysica acta. Molecular cell research.

[56]  Danzhi Huang,et al.  METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes , 2020, bioRxiv.

[57]  Gang Yin,et al.  A newly defined risk signature, consisting of three m6A RNA methylation regulators, predicts the prognosis of ovarian cancer , 2020, Aging.

[58]  Xiaolei Liang,et al.  METTL3-mediated maturation of miR-126-5p promotes ovarian cancer progression via PTEN-mediated PI3K/Akt/mTOR pathway , 2020, Cancer Gene Therapy.

[59]  Peng Liu,et al.  METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP , 2020, Cell biology international.

[60]  T. Rana,et al.  ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment , 2020, Proceedings of the National Academy of Sciences.

[61]  Jinqiu Wang,et al.  The biological function of m6A demethylase ALKBH5 and its role in human disease , 2020, Cancer Cell International.

[62]  Songshan Jiang,et al.  FTO Inhibition Enhances the Antitumor Effect of Temozolomide by Targeting MYC-miR-155/23a Cluster-MXI1 Feedback Circuit in Glioma , 2020, Cancer Research.

[63]  S. Cui,et al.  Gene Signatures and Prognostic Values of m6A RNA Methylation Regulators in Ovarian Cancer , 2020, Cancer control : journal of the Moffitt Cancer Center.

[64]  X. Jia,et al.  WTAP-mediated N6-methyladenosine modification on EGR3 in different types of epithelial ovarian cancer. , 2020, Journal of biological regulators and homeostatic agents.

[65]  D. Matei,et al.  FTO-Dependent N6-Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self-Renewal by Blocking cAMP Signaling , 2020, Cancer Research.

[66]  Chaofeng Hou,et al.  The role of N6-methyladenosine (m6A) modification in the regulation of circRNAs , 2020, Molecular Cancer.

[67]  Lei Wu,et al.  YTHDF2, a protein repressed by miR-145, regulates proliferation, apoptosis, and migration in ovarian cancer cells , 2020, Journal of Ovarian Research.

[68]  Yue Huang,et al.  Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. , 2020, Cancer cell.

[69]  Shulin Zhou,et al.  RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF‐κB pathway , 2020, Journal of cellular and molecular medicine.

[70]  Congjian Xu,et al.  Identification of WTAP-related genes by weighted gene co-expression network analysis in ovarian cancer , 2020, Journal of Ovarian Research.

[71]  D. Deng,et al.  Chidamide increases the sensitivity of Non-small Cell Lung Cancer to Crizotinib by decreasing c-MET mRNA methylation , 2020, bioRxiv.

[72]  A. Caflisch,et al.  Small‐Molecule Inhibitors of METTL3, the Major Human Epitranscriptomic Writer , 2020, ChemMedChem.

[73]  Na Li,et al.  METTL3 serves an oncogenic role in human ovarian cancer cells partially via the AKT signaling pathway , 2020, Oncology letters.

[74]  Fang Wang,et al.  The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation , 2020, Nucleic acids research.

[75]  M. Miloso,et al.  3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line. , 2019, Bioorganic & medicinal chemistry.

[76]  Shiqing Ma,et al.  Epigenetic Regulation of m6A Modifications in Human Cancer , 2019, Molecular therapy. Nucleic acids.

[77]  Jinjian Yang,et al.  Mettl14 inhibits bladder TIC self-renewal and bladder tumorigenesis through N6-methyladenosine of Notch1 , 2019, Molecular Cancer.

[78]  Megan Cully Chemical inhibitors make their RNA epigenetic mark , 2019, Nature Reviews Drug Discovery.

[79]  Zhike Lu,et al.  N6-methyladenosine RNA modification–mediated cellular metabolism rewiring inhibits viral replication , 2019, Science.

[80]  Jian-hua Yang,et al.  WTAP is a prognostic marker of high-grade serous ovarian cancer and regulates the progression of ovarian cancer cells , 2019, OncoTargets and therapy.

[81]  E. Robertson,et al.  EBV epitranscriptome reprogramming by METTL14 is critical for viral-associated tumorigenesis , 2019, PLoS pathogens.

[82]  L. You,et al.  WT1 associated protein promotes metastasis and chemo-resistance to gemcitabine by stabilizing Fak mRNA in pancreatic cancer. , 2019, Cancer letters.

[83]  Cancer control , 2019, Chronic Care Nursing.

[84]  M. Wei,et al.  TROAP Promotes Breast Cancer Proliferation and Metastasis , 2019, BioMed research international.

[85]  Huan Wu,et al.  ALKBH5 inhibited autophagy of epithelial ovarian cancer through miR-7 and BCL-2 , 2019, Journal of Experimental & Clinical Cancer Research.

[86]  Lin Zhang,et al.  N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance. , 2019, Cancer research.

[87]  Liang Ming,et al.  The role of m6A RNA methylation in cancer. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[88]  Hualiang Jiang,et al.  Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. , 2019, Cancer cell.

[89]  S. Lockwood,et al.  Ovarian Cancer: An Integrated Review. , 2019, Seminars in oncology nursing.

[90]  Q. Lan,et al.  The Critical Role of RNA m6A Methylation in Cancer. , 2019, Cancer research.

[91]  Danyang Yu,et al.  METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition. , 2018, Gynecologic oncology.

[92]  Jianjun Chen,et al.  IGF2BP1 promotes SRF-dependent transcription in cancer in a m6A- and miRNA-dependent manner , 2018, Nucleic acids research.

[93]  Tim Hui-Ming Huang,et al.  Cross-talk among writers, readers, and erasers of m6A regulates cancer growth and progression , 2018, Science Advances.

[94]  Yizhen Wang,et al.  Epigallocatechin gallate targets FTO and inhibits adipogenesis in an mRNA m6A-YTHDF2-dependent manner , 2018, International Journal of Obesity.

[95]  Gunter Meister,et al.  Interactions, localization, and phosphorylation of the m6A generating METTL3–METTL14–WTAP complex , 2018, RNA.

[96]  Yue Sheng,et al.  METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification. , 2017, Cell stem cell.

[97]  Tao Pan,et al.  Dynamic RNA Modifications in Gene Expression Regulation , 2017, Cell.

[98]  Feng Liu,et al.  METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6‐methyladenosine‐dependent primary MicroRNA processing , 2017, Hepatology.

[99]  Chuan He,et al.  FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. , 2017, Cancer cell.

[100]  Chuan He,et al.  N6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions , 2015, Nature.

[101]  Cheng Luo,et al.  Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5 , 2014, Nucleic acids research.

[102]  Samir Adhikari,et al.  Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase , 2014, Cell Research.

[103]  Miao Yu,et al.  A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation , 2013, Nature chemical biology.

[104]  Yun-Gui Yang,et al.  N6-methyl-adenosine (m6A) in RNA: An Old Modification with A Novel Epigenetic Function , 2012, Genom. Proteom. Bioinform..

[105]  Beverley Balkau,et al.  Variation in FTO contributes to childhood obesity and severe adult obesity , 2007, Nature Genetics.

[106]  F. Rottman,et al.  An in vitro system for accurate methylation of internal adenosine residues in messenger RNA. , 1988, Science.

[107]  R. Desrosiers,et al.  Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[108]  Chang Shu,et al.  Small-molecule exhibits anti-tumor activity by targeting the RNA m6A reader IGF2BP3 in ovarian cancer. , 2023, American journal of cancer research.

[109]  F. Rottman,et al.  N6-adenosine methylation in mRNA: substrate specificity and enzyme complexity. , 1994, Biochimie.

[110]  C. Kahana,et al.  Nucleic Acids Research Identification and mapping of N6-methyladenosine containing sequences in Simian Virus 40 RNA , 2022 .