RNA methylation-related inhibitors: Biological basis and therapeutic potential for cancer therapy

Abstract

• In this paper, several important types of RNA modifications and their related regulatory factors are systematically summarised.

• Several regulatory factors related to RNA modification types were associated with cancer progression, and their relationships with cancer cell migration, invasion, drug resistance and immune environment were summarised.

• In this paper, the inhibitors targeting different regulators that have been proposed in recent studies are summarised in detail, which is of great significance for the development of RNA modification regulators and cancer treatment in the future.

Keywords

cancer / drug resistance / inhibitor / RNA methylation

References

[1] SunH, WangX, ZhaiS. The rational design and biological mechanisms of nanoradiosensitizers. Nanomaterials (Basel). 2020;10(3):504.

[2] HuSC, YangJ, ChenC, Song JR, PanWD. Design, synthesis of novel tetrandrine-14-L-amino acid and tetrandrine-14-L-amino acid-urea derivatives as potential anti-cancer agents. Molecules. 2020;25(7):1738.

[3] ChenMH, LuSN, ChenCH, et al. How may ramucirumab help improve treatment outcome for patients with gastrointestinal cancers?Cancers (Basel). 2021;13(14):3536.

[4] SungH, FerlayJ, SiegelRL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.

[5] QiJ, LiM, WangL, et al. National and subnational trends in cancer burden in China, 2005-20: an analysis of national mortality surveillance data. Lancet Public Health. 2023;8(12):e943-e955.

[6] VranesV, Rajkovic N, LiX, et al. Size and shape filtering of malignant cell clusters within breast tumors identifies scattered individual epithelial cells as the most valuable histomorphological clue in the prognosis of distant metastasis risk. Cancers (Basel). 2019;11(10):1615.

[7] NombelaP, Miguel-Lopez B, BlancoS. The role of m(6)A, m(5)C and Psi RNA modifications in cancer: novel therapeutic opportunities. Mol Cancer. 2021;20(1):18.

[8] MarshJW, Hayward RJ, ShettyAC, MahurkarA, Humphrys MS, MyersGSA. Bioinformatic analysis of bacteria and host cell dual RNA-sequencing experiments. Brief Bioinform. 2018;19(6):1115-1129.

[9] YanY, PengJ, LiangQ, et al. Dynamic m6A-ncRNAs association and their impact on cancer pathogenesis, immune regulation and therapeutic response. Genes Dis. 2023;10(1):135-150.

[10] HeJ, LiuF, ZhangZ. Functions of N6-methyladenosine in cancer metabolism: from mechanism to targeted therapy. Biomark Res. 2023;11(1):40.

[11] TangJ, ZhangJ, LuY, et al. Novel insights into the multifaceted roles of m(6)A-modified lncRNAs in cancers: biological functions and therapeutic applications. Biomark Res. 2023;11(1):42.

[12] JinD, GuoJ, WuY, et al. m(6)A mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol. 2019;12(1):135.

[13] GeulaS, Moshitch-Moshkovitz S, DominissiniD, et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 2015;347(6225):1002-1006.

[14] WengH, HuangH, WuH, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification. Cell Stem Cell. 2018;22(2):191-205.e199.

[15] JaninM, Ortiz-Barahona V, de MouraMC, et al. Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. Acta Neuropathol. 2019;138(6):1053-1074.

[16] SuR, DongL, LiC, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172(1-2):90-105.e123.

[17] GuoB, ZhangH, WangJ, et al. Identification of the signature associated with m(6)A RNA methylation regulators and m(6)A-related genes and construction of the risk score for prognostication in early-stage lung adenocarcinoma. Front Genet. 2021;12:656114.

[18] ZhengH, LiS, ZhangX, Sui N. Functional implications of active N(6)-methyladenosine in plants. Front Cell Dev Biol. 2020;8:291.

[19] ZhouZ, LvJ, YuH, et al. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol Cancer. 2020;19(1):104.

[20] ZhaoY, ShiY, ShenH, Xie W. m(6)A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020;13(1):35.

[21] SunT, WuR, MingL. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613.

[22] MitchellCA, LimSG, StreetAM. High dose intravenous gammaglobulin in immune haematological disease. Dev Biol Stand. 1987;67:267-272.

[23] KeS, Pandya-Jones A, SaitoY, et al. m(6)A mRNA modifications are deposited in nascent pre-mRNA and are not required for splicing but do specify cytoplasmic turnover. Genes Dev. 2017;31(10):990-1006.

[24] WangP, Doxtader KA, NamY. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell. 2016;63(2):306-317.

[25] WangX, FengJ, XueY, et al. Structural basis of N(6)-adenosine methylation by the METTL3‒METTL14 complex. Nature. 2016;534(7608):575-578.

[26] LanN, LuY, ZhangY, et al. FTO—a common genetic basis for obesity and cancer. Front Genet. 2020;11:559138.

[27] WangJ, WangJ, GuQ, et al. The biological function of m6A demethylase ALKBH5 and its role in human disease. Cancer Cell Int. 2020;20:347.

[28] FortuineR. Empirical healing among the Alaska Natives. An historical perspective. Arctic Med Res. 1988;47(suppl 1):296-302.

[29] XueC, ChuQ, ZhengQ, et al. Role of main RNA modifications in cancer: n(6)-methyladenosine, 5-methylcytosine, and pseudouridine. Signal Transduct Target Ther. 2022;7(1):142.

[30] BohnsackKE, Hobartner C, BohnsackMT. Eukaryotic 5-methylcytosine (m(5)C) RNA methyltransferases: mechanisms, cellular functions, and links to disease. Genes (Basel). 2019;10(2):102.

[31] LiuL, SongB, MaJ, et al. Bioinformatics approaches for deciphering the epitranscriptome: recent progress and emerging topics. Comput Struct Biotechnol J. 2020;18:1587-1604.

[32] ChengMY, YouXJ, DingJH, et al. Novel dual methylation of cytidines in the RNA of mammals. Chem Sci. 2021;12(23):8149-8156.

[33] LiM, TaoZ, ZhaoY, et al. 5-Methylcytosine RNA methyltransferases and their potential roles in cancer. J Transl Med. 2022;20(1):214.

[34] ZhangQ, LiuF, ChenW, et al. The role of RNA m(5)C modification in cancer metastasis. Int J Biol Sci. 2021;17(13):3369-3380.

[35] ChenZ, ZhuW, ZhuS, et al. METTL1 promotes hepatocarcinogenesis via m(7) G tRNA modification-dependent translation control. Clin Transl Med. 2021;11(12):e661.

[36] MaJ, HanH, HuangY, et al. METTL1/WDR4-mediated m(7)G tRNA modifications and m(7)G codon usage promote mRNA translation and lung cancer progression. Mol Ther. 2021;29(12):3422-3435.

[37] YingX, LiuB, YuanZ, et al. METTL1-m(7) G-EGFR/EFEMP1 axis promotes the bladder cancer development. Clin Transl Med. 2021;11(12):e675.

[38] KatsaraO, Schneider RJ. m(7)G tRNA modification reveals new secrets in the translational regulation of cancer development. Mol Cell. 2021;81(16):3243-3245.

[39] LuoY, YaoY, WuP, ZiX, SunN, HeJ. The potential role of N(7)-methylguanosine (m7G) in cancer. J Hematol Oncol. 2022;1(1):63.

[40] TrotmanJB, Giltmier AJ, MukherjeeC, SchoenbergDR. RNA guanine-7 methyltransferase catalyzes the methylation of cytoplasmically recapped RNAs. Nucleic Acids Res. 2017;45(18):10726-10739.

[41] HaagS, Kretschmer J, BohnsackMT. WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA. RNA. 2015;21(2):180-187.

[42] DaiX, WangT, GonzalezG, Wang Y. Identification of YTH domain-containing proteins as the readers for N1-methyladenosine in RNA. Anal Chem. 2018;90(11):6380-6384.

[43] ZhangC, JiaG. Reversible RNA modification N(1)-methyladenosine (m(1)A) in mRNA and tRNA. Genom Proteom Bioinform. 2018;16(3):155-161.

[44] DominissiniD, Nachtergaele S, Moshitch-MoshkovitzS, et al. The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016;530(7591):441-446.

[45] SchwartzS, Bernstein DA, MumbachMR, et al. Transcriptome-wide mapping reveals widespread dynamic-regulated pseudouridylation of ncRNA and mRNA. Cell. 2014;159(1):148-162.

[46] SpenkuchF, Motorin Y, HelmM. Pseudouridine: still mysterious, but never a fake (uridine)!. RNA Biol. 2014;11(12):1540-1554.

[47] HurS, StroudRM, Finer-MooreJ. Substrate recognition by RNA 5-methyluridine methyltransferases and pseudouridine synthases: a structural perspective. J Biol Chem. 2006;281(51):38969-38973.

[48] LiX, MaS, YiC. Pseudouridine: the fifth RNA nucleotide with renewed interests. Curr Opin Chem Biol. 2016;33:108-116.

[49] TorsinLI, Petrescu GED, SaboAA, et al. Editing and chemical modifications on non-coding RNAs in cancer: a new tale with clinical significance. Int J Mol Sci. 2021;22(2):581.

[50] KarijolichJ, YuYT. Converting nonsense codons into sense codons by targeted pseudouridylation. Nature. 2011;474(7351):395-398.

[51] CarlileTM, Rojas-Duran MF, ZinshteynB, ShinH, Bartoli KM, GilbertWV. Pseudouridine profiling reveals regulated mRNA pseudouridylation in yeast and human cells. Nature. 2014;515(7525):143-146.

[52] ZhangW, Eckwahl MJ, ZhouKI, PanT. Sensitive and quantitative probing of pseudouridine modification in mRNA and long noncoding RNA. RNA. 2019;25(9):1218-1225.

[53] PenzoM, Guerrieri AN, ZacchiniF, TrereD, Montanaro L. RNA pseudouridylation in physiology and medicine: for better and for worse. Genes (Basel). 2017;8(11):301.

[54] SunT, WuZ, WangX, et al. LNC942 promoting METTL14-mediated m(6)A methylation in breast cancer cell proliferation and progression. Oncogene. 2020;39(31):5358-5372.

[55] GongY, JiangQ, LiuL, et al. METTL3-mediated m6A modification promotes processing and maturation of pri-miRNA-19a to facilitate nasopharyngeal carcinoma cell proliferation and invasion. Physiol Genomics. 2022;54(9):337-349.

[56] WangXK, ZhangYW, WangCM, et al. METTL16 promotes cell proliferation by up-regulating cyclin D1 expression in gastric cancer. J Cell Mol Med. 2021;25(14):6602-6617.

[57] ShiY, FanS, WuM, et al. YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun. 2019;10(1):4892.

[58] ZhangS, ZhaoBS, ZhouA, et al. m(6)A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31(4):591-606.e596.

[59] MaX, LongC, WangF, et al. METTL3 attenuates proliferative vitreoretinopathy and epithelial‒mesenchymal transition of retinal pigment epithelial cells via wnt/beta-catenin pathway. J Cell Mol Med. 2021;25(9):4220-4234.

[60] ZhangL, LuoX, QiaoS. METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma. Br J Cancer. 2022;127(1):30-42.

[61] YangZ, CaiZ, YangC, Luo Z, BaoX. ALKBH5 regulates STAT3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6A-YTHDF2-dependent manner. EBioMedicine. 2022;80:104019.

[62] SongW, FeiF, QiaoF, et al. ALKBH5-mediated N(6)-methyladenosine modification of TRERNA1 promotes DLBCL proliferation via p21 downregulation. Cell Death Discov. 2022;8(1):25.

[63] ZhongL, LiaoD, ZhangM, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252-261.

[64] HuY, ChenC, TongX, et al. NSUN2 modified by SUMO-2/3 promotes gastric cancer progression and regulates mRNA m5C methylation. Cell Death Dis. 2021;12(9):842.

[65] LuoG, XuW, ChenX, et al. NSUN2-mediated RNA m(5)C modification modulates uveal melanoma cell proliferation and migration. Epigenetics. 2022;17(8):922-933.

[66] XueS, XuH, SunZ, et al. Depletion of TRDMT1 affects 5-methylcytosine modification of mRNA and inhibits HEK293 cell proliferation and migration. Biochem Biophys Res Commun. 2019;520(1):60-66.

[67] WangJZ, ZhuW, HanJ, et al. The role of the HIF-1alpha/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer. Cancer Commun (Lond). 2021;41(7):560-575.

[68] ZhaoY, ZhaoQ, KaboliPJ, et al. m1A regulated genes modulate PI3K/AKT/mTOR and ErbB pathways in gastrointestinal cancer. Transl Oncol. 2019;12(10):1323-1333.

[69] LiuY, ZhouJ, LiX, et al. tRNA-m(1)A modification promotes T cell expansion via efficient MYC protein synthesis. Nat Immunol. 2022;23(10):1433-1444.

[70] WakuT, Nakajima Y, YokoyamaW, et al. NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner. J Cell Sci. 2016;129(12):2382-2393.

[71] XiaP, ZhangH, XuK, et al. MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma. Cell Death Dis. 2021;12(7):691.

[72] HuangY, MaJ, YangC, et al. METTL1 promotes neuroblastoma development through m(7)G tRNA modification and selective oncogenic gene translation. Biomark Res. 2022;10(1):68.

[73] HanH, YangC, MaJ, et al. N(7)-methylguanosine tRNA modification promotes esophageal squamous cell carcinoma tumorigenesis via the RPTOR/ULK1/autophagy axis. Nat Commun. 2022;13(1):1478.

[74] KanG, WangZ, ShengC, et al. Dual inhibition of DKC1 and MEK1/2 synergistically restrains the growth of colorectal cancer cells. Adv Sci (Weinh). 2021;8(10):2004344.

[75] ZhangQ, FeiS, ZhaoY, et al. PUS7 promotes the proliferation of colorectal cancer cells by directly stabilizing SIRT1 to activate the Wnt/beta-catenin pathway. Mol Carcinog. 2023;62(2):160-173.

[76] LiuSY, ZhaoZY, QiaoZ, Li SM, ZhangWN. LncRNA PCAT1 interacts with DKC1 to regulate proliferation, invasion and apoptosis in NSCLC Cells via the VEGF/AKT/Bcl2/Caspase9 pathway. Cell Transplant. 2021;30:963689720986071.

[77] GarusA, Autexier C. Dyskerin: an essential pseudouridine synthase with multifaceted roles in ribosome biogenesis, splicing, and telomere maintenance. RNA. 2021;27(12):1441-1458.

[78] ZhangDY, MingGL, SongH. PUS7: a targetable epitranscriptomic regulator of glioblastoma growth. Trends Pharmacol Sci. 2021;42(12):976-978.

[79] KurimotoR, ChibaT, ItoY, et al. The tRNA pseudouridine synthase TruB1 regulates the maturation of let-7 miRNA. EMBO J. 2020;39(20):e104708.

[80] LiX, XiongW, LongX, et al. Inhibition of METTL3/m6A/miR126 promotes the migration and invasion of endometrial stromal cells in endometriosisdagger. Biol Reprod. 2021;105(5):1221-1233.

[81] LiuX, XiaoM, ZhangL, et al. The m6A methyltransferase METTL14 inhibits the proliferation, migration, and invasion of gastric cancer by regulating the PI3K/AKT/mTOR signaling pathway. J Clin Lab Anal. 2021;35(3):e23655.

[82] GuoX, LiK, JiangW, et al. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol Cancer. 2020;19(1):91.

[83] YuH, YangX, TangJ, et al. ALKBH5 inhibited cell proliferation and sensitized bladder cancer cells to cisplatin by m6A-CK2alpha-mediated glycolysis. Mol Ther Nucleic Acids. 2021;23:27-41.

[84] PengW, LiJ, ChenR, et al. Upregulated METTL3 promotes metastasis of colorectal cancer via miR-1246/SPRED2/MAPK signaling pathway. J Exp Clin Cancer Res. 2019;38(1):393.

[85] WuH, LiF, ZhuR. miR-338-5p inhibits cell growth and migration via inhibition of the METTL3/m6A/c-Myc pathway in lung cancer. Acta Biochim Biophys Sin (Shanghai). 2021;53(3):304-316.

[86] NiuY, LinZ, WanA, et al. RNA N6-methyladenosine demethylase FTO promotes breast tumor progression through inhibiting BNIP3. Mol Cancer. 2019;18(1):46.

[87] SunG, MaS, ZhengZ, et al. Multi-omics analysis of expression and prognostic value of NSUN members in prostate cancer. Front Oncol. 2022;12:965571.

[88] YanJ, LiuJ, HuangZ, Huang W, LvJ. FOXC2-AS1 stabilizes FOXC2 mRNA via association with NSUN2 in gastric cancer cells. Hum Cell. 2021;34(6):1755-1764.

[89] WangL, ZhangJ, SuY, et al. Distinct roles of m(5)C RNA methyltransferase NSUN2 in major gynecologic cancers. Front Oncol. 2022;12:786266.

[90] ChenL, DingJ, WangB, et al. RNA methyltransferase NSUN2 promotes hypopharyngeal squamous cell carcinoma proliferation and migration by enhancing TEAD1 expression in an m(5)C-dependent manner. Exp Cell Res. 2021;404(2):112664.

[91] WangN, ChenRX, DengMH, et al. m(5)C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization. Cell Death Dis. 2023;14(2):139.

[92] WangB, NiuL, WangZ, Zhao Z. RNA m1A methyltransferase TRMT6 predicts poorer prognosis and promotes malignant behavior in glioma. Front Mol Biosci. 2021;8:692130.

[93] ChenZ, QiM, ShenB, et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 2019;47(5):2533-2545.

[94] ZhaoY, KongL, PeiZ, et al. m7G methyltransferase METTL1 promotes post-ischemic angiogenesis via promoting VEGFA mRNA translation. Front Cell Dev Biol. 2021;9:642080.

[95] PandolfiniL, Barbieri I, BannisterAJ, et al. METTL1 promotes let-7 microRNA processing via m7G methylation. Mol Cell. 2019;74(6):1278-1290.e1279.

[96] BalzeauJ, Menezes MR, CaoS, HaganJP. The LIN28/let-7 pathway in cancer. Front Genet. 2017;8:31.

[97] BellodiC, Krasnykh O, HaynesN, et al. Loss of function of the tumor suppressor DKC1 perturbs p27 translation control and contributes to pituitary tumorigenesis. Cancer Res. 2010;70(14):6026-6035.

[98] RocchiL, Pacilli A, SethiR, et al. Dyskerin depletion increases VEGF mRNA internal ribosome entry site-mediated translation. Nucleic Acids Res. 2013;41(17):8308-8318.

[99] MiaoFA, ChuK, ChenHR, et al. Increased DKC1 expression in glioma and its significance in tumor cell proliferation, migration and invasion. Invest New Drugs. 2019;37(6):1177-1186.

[100] ZengH, PanJ, HuC, et al. SNHG25 facilitates SNORA50C accumulation to stabilize HDAC1 in neuroblastoma cells. Cell Death Dis. 2022;13(7):597.

[101] ChenS, LiQH, ChenX, et al. SNORA70E promotes the occurrence and development of ovarian cancer through pseudouridylation modification of RAP1B and alternative splicing of PARPBP. J Cell Mol Med. 2022;26(20):5150-5164.

[102] PanX, HongX, LiS, MengP, XiaoF. METTL3 promotes adriamycin resistance in MCF-7 breast cancer cells by accelerating pri-microRNA-221-3p maturation in a m6A-dependent manner. Exp Mol Med. 2021;53(1):91-102.

[103] ZhangH, WangSQ, WangL, et al. m6A methyltransferase METTL3-induced lncRNA SNHG17 promotes lung adenocarcinoma gefitinib resistance by epigenetically repressing LATS2 expression. Cell Death Dis. 2022;13(7):657.

[104] PearsonRW, PallerAS. Dermolytic (dystrophic) epidermolysis bullosa inversa. Arch Dermatol. 1988;124(4):544-547.

[105] ChenY, LuZ, QiC, et al. N(6)-methyladenosine-modified TRAF1 promotes sunitinib resistance by regulating apoptosis and angiogenesis in a METTL14-dependent manner in renal cell carcinoma. Mol Cancer. 2022;21(1):111.

[106] WangZ, HeJ, BachDH, et al. Induction of m(6)A methylation in adipocyte exosomal lncRNAs mediates myeloma drug resistance. J Exp Clin Cancer Res. 2022;41(1):4.

[107] SaR, LiangR, QiuX, HeZ, LiuZ, ChenL. IGF2BP2-dependent activation of ERBB2 signaling contributes to acquired resistance to tyrosine kinase inhibitor in differentiation therapy of radioiodine-refractory papillary thyroid cancer. Cancer Lett. 2022;527:10-23.

[108] OuB, LiuY, GaoZ, et al. Senescent neutrophils-derived exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022;13(10):905.

[109] NieS, ZhangL, LiuJ, et al. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer. J Exp Clin Cancer Res. 2021;40(1):284.

[110] ZhanY, LiuY, YangR, et al. CircPTEN suppresses human clear cell renal carcinoma progression and resistance to mTOR inhibitors by targeting epigenetic modification. Drug Resist Updat. 2023;71:101003.

[111] LiF, ZhengZ, ChenW, et al. Regulation of cisplatin resistance in bladder cancer by epigenetic mechanisms. Drug Resist Updat. 2023;68:100938.

[112] LinX, YeR, LiZ, et al. KIAA1429 promotes tumorigenesis and gefitinib resistance in lung adenocarcinoma by activating the JNK/MAPK pathway in an m(6)A-dependent manner. Drug Resist Updat. 2023;66:100908.

[113] LiuZ, ZhengN, LiJ, et al. N6-methyladenosine-modified circular RNA QSOX1 promotes colorectal cancer resistance to anti-CTLA-4 therapy through induction of intratumoral regulatory T cells. Drug Resist Updat. 2022;65:100886.

[114] BlancoS, Bandiera R, PopisM, et al. Stem cell function and stress response are controlled by protein synthesis. Nature. 2016;534(7607):335-340.

[115] LiN, KangY, WangL, et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci U S A. 2020;117(33):20159-20170.

[116] OkamotoM, Fujiwara M, HoriM, et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 2014;10(9):e1004639.

[117] GaoW, ChenL, LinL, et al. SIAH1 reverses chemoresistance in epithelial ovarian cancer via ubiquitination of YBX-1. Oncogenesis. 2022;11(1):13.

[118] LiuY, YangC, ZhaoY, Chi Q, WangZ, SunB. Overexpressed methyltransferase-like 1 (METTL1) increased chemosensitivity of colon cancer cells to cisplatin by regulating miR-149-3p/S100A4/p53 axis. Aging (Albany NY). 2019;11(24):12328-12344.

[119] HuangM, LongJ, YaoZ, et al. METTL1-mediated m7G tRNA modification promotes lenvatinib resistance in hepatocellular carcinoma. Cancer Res. 2023;83(1):89-102.

[120] ChenB, JiangW, HuangY, et al. N(7)-methylguanosine tRNA modification promotes tumorigenesis and chemoresistance through WNT/beta-catenin pathway in nasopharyngeal carcinoma. Oncogene. 2022;41(15):2239-2253.

[121] MoradG, Helmink BA, SharmaP, WargoJA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184(21):5309-5337.

[122] WanW, AoX, ChenQ, et al. METTL3/IGF2BP3 axis inhibits tumor immune surveillance by upregulating N(6)-methyladenosine modification of PD-L1 mRNA in breast cancer. Mol Cancer. 2022;21(1):60.

[123] SongH, SongJ, ChengM, et al. METTL3-mediated m(6)A RNA methylation promotes the anti-tumour immunity of natural killer cells. Nat Commun. 2021;12(1):5522.

[124] DongL, ChenC, ZhangY, et al. The loss of RNA N(6)-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8(+) T cell dysfunction and tumor growth. Cancer Cell. 2021;39(7):945-957.e910.

[125] QiuX, YangS, WangS, et al. M(6)A demethylase ALKBH5 regulates PD-L1 expression and tumor immunoenvironment in intrahepatic cholangiocarcinoma. Cancer Res. 2021;81(18):4778-4793.

[126] YangS, WeiJ, CuiYH, et al. m(6)A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade. Nat Commun. 2019;10(1):2782.

[127] JinS, LiJ, ShenY, Wu Y, ZhangZ, MaH. RNA 5-methylcytosine regulator NSUN3 promotes tumor progression through regulating immune infiltration in head and neck squamous cell carcinoma. Oral Dis. 2022;30(2):313-328.

[128] TongX, XiangY, HuY, et al. NSUN2 promotes tumor progression and regulates immune infiltration in nasopharyngeal carcinoma. Front Oncol. 2022;12:788801.

[129] GuX, ZhouH, ChuQ, ZhengQ, WangJ, Zhu H. Uncovering the association between m(5)C regulator-mediated methylation modification patterns and tumour microenvironment infiltration characteristics in hepatocellular carcinoma. Front Cell Dev Biol. 2021;9:727935.

[130] XuX, ZhaoY, YingY, et al. m7G-related genes-NCBP2 and EIF4E3 determine immune contexture in head and neck squamous cell carcinoma by regulating CCL4/CCL5 expression. Mol Carcinog. 2023;62(8):1091-1106.

[131] XuF, CaiD, LiuS, et al. N7-methylguanosine regulatory genes well represented by METTL1 define vastly different prognostic, immune and therapy landscapes in adrenocortical carcinoma. Am J Cancer Res. 2023;13(2):538-568.

[132] ShiH, WeiJ, HeC. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74(4):640-650.

[133] MaS, ChenC, JiX, et al. The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol. 2019;12(1):121.

[134] ChenB, YeF, YuL, et al. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J Am Chem Soc. 2012;134(43):17963-17971.

[135] YanF, Al-Kali A, ZhangZ, et al. A dynamic N(6)-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Res. 2018;28(11):1062-1076.

[136] CuiQ, ShiH, YeP, et al. m(6)A RNA methylation regulates the self-renewal and tumorigenesis of glioblastoma stem cells. Cell Rep. 2017;18(11):2622-2634.

[137] HuangY, SuR, ShengY, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35(4):677-691.e610.

[138] SuR, DongL, LiY, et al. Targeting FTO suppresses cancer stem cell maintenance and immune evasion. Cancer Cell. 2020;38(1):79-96.e11.

[139] XieG, WuXN, LingY, et al. A novel inhibitor of N (6)-methyladenosine demethylase FTO induces mRNA methylation and shows anti-cancer activities. Acta Pharm Sin B. 2022;12(2):853-866.

[140] MalacridaA, Di Domizio A, BentivegnaA, et al. MV1035 overcomes temozolomide resistance in patient-derived glioblastoma stem cell lines. Biology (Basel). 2022;11(1):70.

[141] SelbergS, SeliN, KankuriE, Karelson M. Rational design of novel anticancer small-molecule RNA m6A demethylase ALKBH5 inhibitors. ACS Omega. 2021;6(20):13310-13320.

[142] FangZ, MuB, LiuY, et al. Discovery of a potent, selective and cell active inhibitor of m(6)A demethylase ALKBH5. Eur J Med Chem. 2022;238:114446.

[143] TakahashiH, HaseH, YoshidaT, et al. Discovery of two novel ALKBH5 selective inhibitors that exhibit uncompetitive or competitive type and suppress the growth activity of glioblastoma multiforme. Chem Biol Drug Des. 2022;100(1):1-12.

[144] AlshakerH, WangQ, BrewerD, Pchejetski D. Transcriptome-wide effects of sphingosine kinases knockdown in metastatic prostate and breast cancer cells: implications for therapeutic targeting. Front Pharmacol. 2019;10:303.

[145] ZhengX, LiW, RenL, et al. The sphingosine kinase-1/sphingosine-1-phosphate axis in cancer: potential target for anticancer therapy. Pharmacol Ther. 2019;195:85-99.

[146] ShibataT, WatariK, KawaharaA, et al. Targeting phosphorylation of Y-box-binding protein YBX1 by TAS0612 and everolimus in overcoming antiestrogen resistance. Mol Cancer Ther. 2020;19(3):882-894.

[147] SchaeferM, Hagemann S, HannaK, LykoF. Azacytidine inhibits RNA methylation at DNMT2 target sites in human cancer cell lines. Cancer Res. 2009;69(20):8127-8132.

[148] RocchiL, Barbosa AJ, OnofrilloC, Del RioA, Montanaro L. Inhibition of human dyskerin as a new approach to target ribosome biogenesis. PLoS One. 2014;9(7):e101971.

[149] FlorestaG, Pistara V, AmataE, et al. Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5'-monophosphate glycosidase. Chem Biol Drug Des. 2018;91(2):519-525.

[150] ArmandoRG, Mengual Gomez DL, JuritzEI, Lorenzano MennaP, Gomez DE. Homology model and docking-based virtual screening for ligands of human dyskerin as new inhibitors of telomerase for cancer treatment. Int J Mol Sci. 2018;19(10):3216.

[151] LongleyDB, HarkinDP, JohnstonPG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-338.

[152] SpedaliereCJ, Mueller EG. Not all pseudouridine synthases are potently inhibited by RNA containing 5-fluorouridine. RNA. 2004;10(2):192-199.

[153] ZhengQ, WangT, LiX, et al. Femtomolar and locus-specific detection of N(6)-methyladenine in DNA by integrating double-hindered replication and nucleic acid-functionalized MB@Zr-MOF. J Nanobiotechnology. 2021;19(1):408.

[154] ZhaoT, SunD, LongK, et al. N(6)-methyladenosine upregulates ribosome biogenesis in environmental carcinogenesis. Sci Total Environ. 2023;881:163428.

[155] LiuT, FengYL, WangRY, et al. Long-term MNNG exposure promotes gastric carcinogenesis by activating METTL3/m6A/miR1184 axis-mediated epithelial-mesenchymal transition. Sci Total Environ. 2024;913:169752.

[156] ChenS, WangX, YanJ, WangZ, QianQ, Wang H. Mechanistic illustration on lipid-metabolism disorders induced by triclosan exposure from the viewpoint of m(6)A-RNA epigenetic modification. Sci Total Environ. 2023;901:165953.

[157] ZhouZ, LiHQ, LiuF. DNA methyltransferase inhibitors and their therapeutic potential. Curr Top Med Chem. 2018;18(28):2448-2457.

[158] SuZ, ZhangY, CaoJ, et al. Hyaluronic acid-FGF2-derived peptide bioconjugates for suppression of FGFR2 and AR simultaneously as an acne antagonist. J Nanobiotechnology. 2023;21(1):55.

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