Open Access Journal Article

The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression

by Haitao Chen a Huilong Li a Wanjin Shi a Hai Qin b,*  and  Lufeng Zheng a,*
a
School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 639 Longmian Road, Nanjing 211198, China
b
Department of Clinical Laboratory, Guizhou Provincial Orthopedic Hospital, No. 206, Sixian Street, Baiyun District, Guiyang City, Guizhou Province, China
*
Author to whom correspondence should be addressed.
CI  2022, 10; 1(2), 10; https://doi.org/10.58567/ci01020001
Received: 2 December 2022 / Accepted: 17 December 2022 / Published: 18 December 2022

Abstract

As a reversible post-transcriptional modification, N6-methyladeno sine is the most common form of RNA modification in eukaryotic mRNA. Cancer stem cells (CSCs), which are a subpopulation of cells with self-renewal ability and differentiation potential, have been regarded to be one of the roots of tumor occurrence, recurrence, and metastasis. Currently, numerous studies have demonstrated that m6A RNA modification is critically implicated in the regulation of CSCs stemness or the CSC-like traits of cancer cells. This review summarized the effects of m6A RNA modification-related enzymes and underlying mechanisms contributing to CSCs or cancer cell stemness, which may provide novel targets and research directions for the specifical elimination of CSCs or cancer cells with stemness.


Copyright: © 2022 by Chen, Li, Shi, Qin and Zheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) (Creative Commons Attribution 4.0 International License). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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ACS Style
Chen, H.; Li, H.; Shi, W.; Qin, H.; Zheng, L. The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression. Cancer Insight, 2022, 1, 10. https://doi.org/10.58567/ci01020001
AMA Style
Chen H, Li H, Shi W, Qin H, Zheng L. The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression. Cancer Insight; 2022, 1(2):10. https://doi.org/10.58567/ci01020001
Chicago/Turabian Style
Chen, Haitao; Li, Huilong; Shi, Wanjin; Qin, Hai; Zheng, Lufeng 2022. "The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression" Cancer Insight 1, no.2:10. https://doi.org/10.58567/ci01020001
APA style
Chen, H., Li, H., Shi, W., Qin, H., & Zheng, L. (2022). The roles of m6A RNA methylation modification in cancer stem cells: new opportunities for cancer suppression. Cancer Insight, 1(2), 10. https://doi.org/10.58567/ci01020001

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References

  1. Bangerter BW, Modestas Z: Proton magnetic resonance study of complex formation between N6-methyladenosine and polyuridylic acid. Biopolymers 1974, 13(3):567-575.
  2. Reichel M, Kö ster T, Staiger D: Marking RNA: m6A writers, readers, and functions in Arabidopsis. Journal of molecular cell biology 2019, 11 (10):899-910.
  3. Oerum S, Meynier V, Catala M, Tisné C: A comprehensive review of m6A/m6Am RNA methyltransferase structures. Nucleic acids research 2021, 49(13):7239-7255.
  4. Batlle E, Clevers H: Cancer stem cells revisited. Nature medicine 2017, 23(10):11 24-1134.
  5. Ma Z, Ji J: N6 -methyladenosine (m6A) RNA modification in cancer stem cells. Stem Cells Dev 2020.
  6. Zhao LY, Song J, Liu Y, Song CX, Yi C: Mapping the epigenetic modifications of DNA and RNA. Protein & cell 2020, 11(11):792 -808.
  7. Selmi T, Hus sain S, Dietmann S, Heiß M, Borland K, Flad S, Carter JM, Dennison R, Huang YL, Kellner S et al : Sequence- and structure -specific cytosine -5 mRNA methylation by NSUN6. Nucleic acids research 2021, 49(2):1006 -1022.
  8. Lu Z, Liu J, Yuan C, Jin M, Quan K, Chu M, Wei C: m(6)A mRNA methylation analysis provides novel insights into heat stress responses in the liver tissue of sheep. enomics 2021, 113(1 Pt 2):484-492.
  9. Huang H, Weng H, Chen J: m(6)A Modification in Coding and Non- coding RNAs: Roles and Therapeu tic Implications in Cancer. Cancer cell 2020, 37(3):270 -288.
  10. Wang P, Feng M, Han , Yin R, Li Y, Yao S, Lu P, Wang Y, Zhang H: RNA m(6)A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis. Front Cell Dev Biol 2021, 9:710964.
  11. Batista PJ, Molinie B, Wang J, Qu K, Zhang J, Li L, Bouley DM, Lujan E, Haddad B, Daneshvar K et al : m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell stem cell 2014, 15(6):707 -719.
  12. Dominissini D, Moshitch- Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob -Hirsch J, Amariglio N, Kupiec M et al: Topology of the human and mouse m6A RNA methylomes revealed by m6A -seq. Nature 2012, 485(7397):201 -206.
  13. Zhang H, Shi X, Huang T, Zhao X, Chen W, u N, Zhang R : Dynamic landscape and evolution of m6A methylation in human. Nucleic acids research 2020, 48(11):6251-6264.
  14. u Z, Du Y, Zhao X, Wang C: Diagnostic, Therapeutic, and Prognostic Value of the m(6)A Writer Complex in Hepatocellular Carcinoma. Front Cell Dev Biol 2022, 10:822011.
  15. Jia , Fu Y, Zhao X, Dai Q, Zheng , Yang Y, Yi C, Lindahl T, Pan T, Yang Y et al : N6-methyladenosine in nuclear RNA is a major substrate of the obesity- associated FTO. Nat Chem Biol 2011, 7(12):885-887.
  16. Huang Y, Yan J, L i Q, Li J, ong S, Zhou H, an J, Jiang H, Jia F, Luo C et al : Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic acids research 2015, 43(1):373 -384.
  17. Loos RJ, Yeo S: The bigger picture of FTO: the first WAS -identified obesity gene. Nature reviews Endocrinology 2014, 10(1):51 -61.
  18. Li Y, Su R, Deng X, Chen Y, Chen J: FTO in cancer: functions, molecular mechanisms, and therapeutic implications. Trends in cancer 2022, 8(7):598 -614.
  19. Marcinkowski M, Pilž ys T, arbic z D, Piwowarski J, Mielecki D, Nowaczyk , Taube M, ielnik M: Effect of Posttranslational Modifications on the Structure and Activity of FTO Demethylase. International journal of molecular sciences 2021, 22(9).
  20. Wang J, Wang J, u Q, Ma Y, Yang Y, Zhu J, Zhang Q: The biological function of m6A demethylase
  21. Qu J, Yan H, Hou Y, Cao W, Liu Y, Zhang E, He J, Cai Z: RNA demethylase ALKBH5 in cancer: from mechanisms to therapeuti c potential. Journal of hematology & oncology 2022, 15(1):8.
  22. Nair L, Zhang W, Laffleur B, Jha MK, Lim J, Lee H, Wu L, Alvarez NS, Liu ZP, Munteanu EL et al : Mechanism of noncoding RNA -associated N(6) -methyladenosine recognition by an RNA processing com plex during IgH DNA recombination. Molecular cell 2021, 81(19):3949-3964.e3947.
  23. Shi H, Wei J, He C: Where, When, and How: Context -Dependent Functions of RNA Methylation Writers, Readers, and Erasers. Molecular cell 2019, 74(4):640 -650.
  24. Du H, Zhao Y , He J, Zhang Y, Xi H, Liu M, Ma J, Wu L: YTHDF2 destabilizes m(6)A -containing RNA through direct recruitment of the CCR4 -NOT deadenylase complex. Nature communications 2016, 7:12626.
  25. Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, Cheng C, Li L, Pi J, Si Y et al: The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic acids research 2020, 48(7):3816 -3831.
  26. Zaccara S, Jaffrey SR: A Unified Model for the Function of YTHDF Proteins in Regulating m(6)A-Modified mRN A. Cell 2020, 181(7):1582 -1595.e1518.
  27. Lan Q, Liu PY, Bell JL, Wang JY, Hüttelmaier S: The Emerging Roles of RNA m(6)A Methylation and Demethylation as Critical Regulators of Tumorigenesis, Drug Sensitivity, and Resistance. Cancer research and treatment : official journal of Korean Cancer Association 2021, 81(13):3431 -3440.
  28. Wallis N, Oberman F, Shurrush K, ermain N, reenwald , ershon T, Pearl T, Abis , Singh V, Singh A et al : Small molecule inhibitor of Igf2bp1 represses Kras and a pro -oncogenic phenotype in cancer cells. RNA biology 2022, 19(1):26 -43.
  29. Han D, Liu J, Chen C, Dong L, Liu Y, Chang R, Huang X, Liu Y, Wang J, Dougherty U et al : Anti -tumour immunity controlled through mRNA m(6)A methylation and YTHDF1 in dendritic cells. Nature 2019, 566(7743):270 -274.
  30. Wan W, Ao X, Chen Q, Yu Y, Ao L, Xing W, uo W, Wu X, Pu C, Hu X et al : METTL3/IF2BP3 axis inhibits tumor immune surveillance by upregulating N(6) -methyladenosine modification of PD -L1 mRNA in breast cancer. Molecular cancer 2022 , 21(1):60.
  31. Chen X, Zhou X, Wang X: m(6)A binding protein YTHDF2 in cancer. Experimental hematology & oncology 2022, 11(1):21.
  32. Ni H, Ruan , Sun C, Yang X, Miao Z, Li J, Chen Y, Qin H, Liu Y, Zheng L et al : Tanshinone IIA inhibits gastric cancer ce ll stemness through inducing ferroptosis. Environ Toxicol 2022, 37(2):192 -200.
  33. Yang Y, Lu Y, Zhang C, uo Q, Zhang W, Wang T, Xia Z, Liu J, Cheng X, Xi T et al : Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferr optosis. Cellular and molecular life sciences : CMLS 2022, 79(7):360.
  34. Yuan Y, Yao H: Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization. J Med Chem 2022, 65(23):15749 -15769.
  35. Liu Y, Liang , Xu H, Dong W, Dong Z, Qiu Z, Zhang Z, Li F, Huang Y, Li Y et al : Tumors exploit FTO -mediated regulation of glycolytic metabolism to evade immune surveillance. Cell metabolism 2021, 33(6):1221 -1233.e1211.
  36. Xu W, Li J, He C, Wen J, Ma H, Ro ng B, Diao J, Wang L, Wang J, Wu F et al : METTL3 regulates heterochromatin in mouse embryonic stem cells. Nature 2021, 591(7849):317-321.
  37. Zheng L, Xiang C, Li X, uo Q, ao L, Ni H, Xia Y, Xi T: STARD13 -correlated ceRNA network -directed inhibition on Y AP/TAZ activity suppresses stemness of breast cancer via co -regulating Hippo and
  38. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun , Sun , Lu Z, Huang Y, Yang C et al : m(6)A RNA Methylation Regulates the Self -Renewal and Tumorigenesis of lioblastoma Stem Cells. Cell reports 2017, 18(11):2622 -2634.
  39. Visvanathan A, Patil V, Abdulla S, Hoheisel JD, Somasundaram K: N ⁶-Methyladenosine Landscape of lioma Stem -Like Cells: METTL3 Is Essential for the Expression of Actively Transcribed enes and Sustenance of the Oncogenic Signaling. enes 2019, 10(2).
  40. Visvanathan A, Patil V, Arora A, Hegde AS, Arivazhagan A, Santosh V , Somasundaram K: Essential role of METTL3 -mediated m(6)A modification in glioma stem- like cells maintenance and radioresistance. Oncogene 2018, 37(4):522 -533.
  41. Chang YZ, Chai RC, Pang B, Chang X, An SY, Zhang KN, Jiang T, Wang YZ: METTL3 enhances the stability of MALAT1 with the assistance of HuR via m6A modification and activates NF -κ B to promote the malignant progression of IDH -wildtype glioma. Cancer letters 2021, 511:36-46.
  42. Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, Chen ZH, Zeng ZL, Wang F, Zheng J et al : METTL3 facilitates tumor progression via an m(6)A -IF2BP2 -dependent mechanism in colorectal carcinoma. Molecular cancer 2019, 18(1):112.
  43. Wang , Dai Y, Li K, Cheng M, Xiong , Wang X, Chen S, Chen Z, Chen J, Xu X et al : Deficiency of Mettl3 i n Bladder Cancer Stem Cells Inhibits Bladder Cancer Progression and Angiogenesis. Front Cell Dev Biol 2021, 9:627706.
  44. ao Q, Zheng J, Ni Z, Sun P, Yang C, Cheng M, Wu M, Zhang X, Yuan L, Zhang Y et al : The m(6)A Methylation -Regulated AFF4 Promotes Self -Renewal of Bladder Cancer Stem Cells. Stem Cells Int 2020, 2020:8849218.
  45. Xie J, Ba J, Zhang M, Wan Y, Jin Z, Yao Y: The m6A methyltransferase METTL3 promotes the stemness and malignant progression of breast cancer by mediating m6A modification on SOX2 . J buon 2021, 26(2):444 -449.
  46. Shi Y, Dou Y, Zhang J, Qi J, Xin Z, Zhang M, Xiao Y, Ci W: The RNA N6 -Methyladenosine Methyltransferase METTL3 Promotes the Progression of Kidney Cancer via N6 -Methyladenosine -Dependent Translational Enhancement of ABCD1. Front Cell Dev Biol 2021, 9:737498.
  47. Li H, Wang C, Lan L, Yan L, Li W, Evans I, Ruiz EJ, Su Q, Zhao , Wu W et al : METTL3 promotes oxaliplatin resistance of gastric cancer CD133+  stem cells by promoting PARP1 mRNA stability. Cellular and molecular life sciences : CMLS 2022, 79(3):135.
  48. Weng H, Huang H, Wu H, Qin X, Zhao BS, Dong L, Shi H, Skibbe J, Shen C, Hu C 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.
  49. Liu Z, Wu K, u S, Wang W, Xie S, Lu T, Li L, Dong C, Wang X, Zhou Y: A methyltransferase -like 14/miR -99a -5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2- mediated epigenetic modulation in esophageal squamous cell carcinoma. Clinical and translational medicine 2021, 11(9):e545.
  50. u C, Wang Z, Zhou N, Li , Kou Y, Luo Y, Wang Y, Yang J, Tian F: Mettl14 inhibits bladder TIC self-renewal and bladder tumor igenesis through N(6)-methyladenosine of Notch1. Molecular cancer 2019, 18(1):168.
  51. Wang Z, Uddin MB, Xie J, Tao H, Zeidler -Erdely PC, Kondo K, Yang C: Chronic Hexavalent Chromium Exposure Upregulates the RNA Methyltransferase METTL3 Expression to Promo te Cell
  52. Wang Y, Zhang L, Sun XL, Lu YC, Chen S, Pei DS, Zhang LS: NRP1 contributes to stemness and potentiates radioresistance via WTAP -mediated m6A meth ylation of Bcl-2 mRNA in breast cancer. Apoptosis : an international journal on programmed cell death 2022.
  53. Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, Chen H, Su R, Yin Z, Li W et al : RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self -Renewal in Acute Myeloid Leukemia. Cell stem cell 2020, 27(1):64 -80 e69.
  54. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, Chen Y, Sulman EP, Xie K, Bögler O et al : m(6)A Demethylase ALKBH5 Maintains Tumorigenicity of lioblast oma Stem-like Cells by Sustaining FOXM1 Expression and Cell Proliferation Program. Cancer cell 2017, 31(4):591 -606.e596.
  55. Kowalski -Chauvel A, Lacore M, Arnauduc F, Delmas C, Toulas C, Cohen -Jonathan -Moyal E, Seva C: The m6A RNA Demethylase ALKBH5 Promo tes Radioresistance and Invasion Capability of lioma Stem Cells. Cancers 2020, 13(1).
  56. Zhang C, Samanta D, Lu H, Bullen JW, Zhang H, Chen I, He X, Semenza L: Hypoxia induces the breast cancer stem cell phenotype by HIF -dependent and ALKBH5- mediated m⁶A- demethylation of NANO mRNA. Proceedings of the National Academy of Sciences of the United States of America 2016, 113(14):E2047 -2056.
  57. Yu T, Yao L, Yin H, Teng Y, Hong M, Wu Q: ALKBH5 Promotes Multiple Myeloma Tumorigenicity through inducing m(6)A -de methylation of SAV1 mRNA and Myeloma Stem Cell Phenotype. International journal of biological sciences 2022, 18(6):2235-2248.
  58. Liu X, Wang Z, Yang Q, Hu X, Fu Q, Zhang X, Li W: RNA Demethylase ALKBH5 Prevents Lung Cancer Progression by Regulating EMT and Stemness via Regulating p53. Front Oncol 2022, 12:858694.
  59. Huang H, Wang Y, Kandpal M, Zhao , Cardenas H, Ji Y, Chaparala A, Tanner EJ, Chen J, Davuluri RV et al : FTO -Dependent N (6) -Methyladenosine Modifications Inhibit Ovarian Cancer Stem Cell Self -Renewal by Blocking cAMP Signaling. Cancer research 2020, 80(16):3200 -3214.
  60. Relier S, Ripoll J, uillorit H, Amalric A, Achour C, Boissiè re F, Vialaret J, Attina A, Debart F, Choquet A et al : FTO -mediated cytoplasmic m(6)A(m) demethylation adjusts ste m-like properties in colorectal cancer cell. Nature communications 2021, 12(1):1716.
  61. Duan X, Yang L, Wang L, Liu Q, Zhang K, Liu S, Liu C, ao Q, Li L, Qin et al : m6A demethylase FTO promotes tumor progression via regulation of lipid metabolism in es ophageal cancer. Cell Biosci 2022, 12(1):60.
  62. Elcheva IA, Wood T, Chiarolanzio K, Chim B, Wong M, Singh V, owda CP, Lu Q, Hafner M, Dovat S et al : RNA -binding protein IF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1 . Leukemia 2020, 34(5):1354 -1363.
  63. Myint K, Chuang LSH, Teh YX, Mawan NA, Shi EJ, Mok MMH, Nuttonmanit N, Matsuo J, Li Y, Yang H et al : Oncofetal protein IF2BP1 regulates IQAP3 expression to maintain stem cell potential in cancer. iScience 2022, 25(10 ):105194.
  64. Dixit D, Prager BC, imple RC, Poh HX, Wang Y, Wu Q, Qiu Z, Kidwell RL, Kim LJY, Xie Q et al : The RNA m6A Reader YTHDF2 Maintains Oncogene Expression and Is a Targetable Dependency in lioblastoma Stem Cells. Cancer discovery 2021, 11(2):480-499.
  65. Zhang C, Huang S, Zhuang H, Ruan S, Zhou Z, Huang K, Ji F, Ma Z, Hou B, He X: YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation. Oncogene 2020, 39(23):4507 -45 18.
  66. Hao L, Wang JM, Liu BQ, Yan J, Li C, Jiang JY, Zhao FY, Qiao HY, Wang HQ: m6A -YTHDF1 -mediated
  67. Paris J, Morgan M, Campos J, Spencer J, Shmakova A, Ivanova I, Mapperley C, Lawson H, Wotherspoon DA, Sepulveda C et al : Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Cell stem cell 2019, 25(1):137-148.e136.
  68. Rong L, Xu Y, Zhang K, Jin L, Liu X: HNRNPA2B1 inhibited SFRP2 and activ ated Wnt-β/ catenin via m6A -mediated miR- 106b-5p processing to aggravate stemness in lung adenocarcinoma. Pathology, research and practice 2022, 233:153794.
  69. Chu M, Wan H, Zhang X: Requirement of splicing factor hnRNP A2B1 for tumorigenesis of melanoma stem cells. Stem Cell Res Ther 2021, 12(1):90.
  70. Su R, Dong L, Li Y, ao M, Han L, Wunderlich M, Deng X, Li H, Huang Y, ao L et al : Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. Cancer cell 2020, 38(1):79 -96.e11.
  71. Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, Ni T, Zhang ZS, Zhang T, Li C et al : Small -Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer cell 2019, 35(4):677 -691.e610.
  72. Huff S, Tiwari SK, onzalez M, Wang Y, Rana TM: m(6)A -RNA Demethylase FTO Inhibitors Impair Self -Renewal in lioblastoma Stem Cells. Acs Chem Biol 2021, 16(2):324-333.
  73. Cao K, Du Y, Bao X, Han M, Su R, Pang J, Liu S, Shi Z, Yan F, Feng S: lutathione -Bioimprinted Nanoparticles Targeting of N6 -methyladenosine F TO Demethylase as a Strategy against Leukemic Stem Cells. Small 2022, 18(13):e2106558.
  74. Qing Y, Dong L, ao L, Li C, Li Y, Han L, Prince E, Tan B, Deng X, Wetzel C et al : R-2- hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FT O/m(6)A/PFKP/LDHB axis. Molecular cell 2021, 81(5):922 -939.e929.
  75. Selberg S, Seli N, Kankuri E, Karelson M: Rational Design of Novel Anticancer Small -Molecule RNA m6A Demethylase ALKBH5 Inhibitors. ACS omega 2021, 6(20):13310-13320.
  76. Yankova E, Black aby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga , Pilka ES, Aspris D, Leggate D, Hendrick A et al : Small -molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature 2021, 593(7860):597 -601.
  77. Xie , Wu XN, Ling Y, Rui Y, Wu D, Zhou J, Li J, Lin S, Peng Q, Li Z et al : A novel inhibitor of N (6)- methyladenosine demethylase FTO induces mRNA methylation and shows anti- cancer activities. Acta pharmaceutica Sinica B 2022, 12(2):853 -866.
  78. Feng S, Qiu , Yang L, Feng L, Fan X, Ren F, Huang K, Chen Y: Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO -mediated activation of mTORC1 and DDIT3 up -regulation. Bioscience reports 2021, 41(1).
  79. Sun K, Du Y, Hou Y, Zhao M, Li J, Du Y, Zhang L, Chen C, Yan g H, Yan F et al : Saikosaponin D exhibits anti -leukemic activity by targeting FTO/m(6)A signaling. Theranostics 2021, 11(12):5831-5846.
  80. Chen WW, Qi JW, Hang Y, Wu JX, Zhou XX, Chen JZ, Wang J, Wang HH: Simvastatin is beneficial to lung cancer progressi on by inducing METTL3 -induced m6A modification on EZH2 mRNA. European review for medical and pharmacological sciences 2020, 24(8):4263 -4270.
  81. Zhao Z, Zeng J, uo Q, Pu K, Yang Y, Chen N, Zhang , Zhao M, Zheng Q, Tang J et al : Berberine Suppresses Stemn ess and Tumorigenicity of Colorectal Cancer Stem -Like Cells by Inhibiting m(6)A Methylation. Front Oncol 2021, 11:775418.