Open Access Journal Article

Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types

by Jiayu Ding a,b,c,1 Hao Shen a,b,c,1 Jiaying Ji a,b,c,1 Jiaxing Li a,b,c Wenbin Kuang a,b,c Zhongrui Shi a,b,c Dawei Wang a,b,c Yuanyuan Chen a,b,c Didi Wan d,* Xiao Wang a,b,c,*  and  Peng Yang a,b,c,* orcid
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Institute of Innovative Drug Discovery and Development, China Pharmaceutical University, Nanjing 211198, China
BGI College & Henan Institute of Medical and Pharmaceutical Sciences Zhengzhou University, Zhengzhou 450052, China
Author to whom correspondence should be addressed.
CI  2024, 36; 3(2), 36;
Received: 27 December 2023 / Accepted: 24 January 2024 / Published Online: 25 January 2024


Adenosine alterations to RNA, which are largely determined by RNA modification writers (RMWs), are critical for cancer growth and progression. These RMWs can catalyze different types of adenosine modifications, such as N6-methyladenosine (m6A), N1-methyladenosine (m1A), alternative polyadenylation (APA), and adenosine-to-inosine (A-to-I) RNA editing. These modifications have profound effects on gene expression and function, such as immune response, cell development. Despite this, the clinical effects of RMW interactive genes on these cancers remain largely unclear. A comprehensive analysis of the clinical impact of these epigenetic regulators in pan-cancer requires further comprehensive exploration. Here, we systematically profiled the molecular and clinical characteristics of 26 RMWs across 33 cancer types using multi-omics datasets and validated the expression level of some RMWs in various cancer lines. Our findings indicated that a majority of RMWs exhibited high expression in diverse cancer types, and this expression was found to be significantly associated with poor patient outcomes. In the genetic alterations, the amplification and mutation of RMWs were the dominant alteration events. Consequently, the RNA Modification Writer Score (RMW score) was established as a means to assess the risk of RMWs in pan-cancer. We found that 27 of 33 cancers had significantly higher scores compared with normal tissues, and it was significantly correlated with prognosis. We also evaluated their impact on the tumor microenvironment and the response to immunotherapy and targeted therapy. These findings verified the important role of RMWs in different aspects of cancer biology, and provided biomarkers and personalized therapeutic targets for cancer.

Copyright: © 2024 by Ding, Shen, Ji, Li, Kuang, Shi, Wang, Chen, Wan, Wang and Yang. 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.


National Key R&D Program of China (2022YFA1303803) , National Natural Science Foundation of China (82073701) , Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (SKLNMZZ202209) , Natural Science Foundation of Jiangsu Province (BK20231013)

Share and Cite

ACS Style
Ding, J.; Shen, H.; Ji, J.; Li, J.; Kuang, W.; Shi, Z.; Wang, D.; Chen, Y.; Wan, D.; Wang, X.; Yang, P. Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types. Cancer Insight, 2024, 3, 36.
AMA Style
Ding J, Shen H, Ji J, Li J, Kuang W, Shi Z, Wang D, Chen Y, Wan D, Wang X, Yang P. Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types. Cancer Insight; 2024, 3(2):36.
Chicago/Turabian Style
Ding, Jiayu; Shen, Hao; Ji, Jiaying; Li, Jiaxing; Kuang, Wenbin; Shi, Zhongrui; Wang, Dawei; Chen, Yuanyuan; Wan, Didi; Wang, Xiao, and et al. 2024. "Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types" Cancer Insight 3, no.2:36.
APA style
Ding, J., Shen, H., Ji, J., Li, J., Kuang, W., Shi, Z., Wang, D., Chen, Y., Wan, D., Wang, X., & Yang, P. (2024). Comprehensive analyses reveal molecular and clinical characteristics of RNA modification writers across 32 cancer types. Cancer Insight, 3(2), 36.

Article Metrics

Article Access Statistics


  1. Mendel, M. et al. (2021). Splice site m(6)A methylation prevents binding of U2AF35 to inhibit RNA splicing. Cell 184, 3125-3142 e3125.
  2. Zhao, B. S., Roundtree, I. A. & He, C. (2017) Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol 18, 31-42.
  3. Ma, S. et al. (2019). The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol 12, 121.
  4. Xu, W. et al. (2022). Dynamic control of chromatin-associated m(6)A methylation regulates nascent RNA synthesis. Mol Cell 82, 1156-1168 e1157.
  5. Yang, Y., Hsu, P. J., Chen, Y. S. & Yang, Y. G. (2018). Dynamic transcriptomic m(6)A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res 28, 616-624.
  6. An, Y. & Duan, H. (2022). The role of m6A RNA methylation in cancer metabolism. Mol Cancer 21, 14.
  7. Safra, M. et al. (2017). The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature 551, 251-255.
  8. Mitschka, S. & Mayr, C. (2022). Context-specific regulation and function of mRNA alternative polyadenylation. Nat Rev Mol Cell Biol 23, 779-796.
  9. Tang, Q. et al. (2021). Adenosine-to-inosine editing of endogenous Z-form RNA by the deaminase ADAR1 prevents spontaneous MAVS-dependent type I interferon responses. Immunity 54, 1961-1975 e1965.
  10. Li, W., Hao, Y., Zhang, X., Xu, S. & Pang, D. (2022). Targeting RNA N(6)-methyladenosine modification: a precise weapon in overcoming tumor immune escape. Mol Cancer 21, 176.
  11. Deng, X. et al. (2018). RNA N(6)-methyladenosine modification in cancers: current status and perspectives. Cell Res 28, 507-517.
  12. Frye, M., Harada, B. T., Behm, M. & He, C. (2018). RNA modifications modulate gene expression during development. Science 361, 1346-1349.
  13. Perlegos, A. E., Shields, E. J., Shen, H., Liu, K. F. & Bonini, N. M. (2022). Mettl3-dependent m(6)A modification attenuates the brain stress response in Drosophila. Nat Commun 13, 5387.
  14. Qi, Z. et al. (2023). N(1)-Methyladenosine modification of mRNA regulates neuronal gene expression and oxygen glucose deprivation/reoxygenation induction. Cell Death Discov 9, 159.
  15. Jiang, X. et al. (2021). The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther 6, 74.
  16. Chen, J., Fang, Y., Xu, Y. & Sun, H. (2022). Role of m6A modification in female infertility and reproductive system diseases. Int J Biol Sci 18, 3592-3604.
  17. Wang, T., Kong, S., Tao, M. & Ju, S. (2020). The potential role of RNA N6-methyladenosine in Cancer progression. Mol Cancer 19, 88.
  18. Wei, J. et al. (2022). FTO mediates LINE1 m(6)A demethylation and chromatin regulation in mESCs and mouse development. Science 376, 968-973.
  19. Yoon, K. J. et al. (2017). Temporal Control of Mammalian Cortical Neurogenesis by m(6)A Methylation. Cell 171, 877-889 e817.
  20. Su, R. et al. (2020). Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. Cancer Cell 38, 79-96 e11.
  21. Zaccara, S., Ries, R. J. & Jaffrey, S. R. (2019). Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol 20, 608-624.
  22. Li, Q. et al. (2021). HIF-1alpha-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal Transduct Target Ther 6, 76.
  23. Li, H. B. et al. (2017). m(6)A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548, 338-342.
  24. Miyake, K. et al. (2023). A cancer-associated METTL14 mutation induces aberrant m6A modification, affecting tumor growth. Cell Rep 42, 112688.
  25. Wang, Y. et al. (2021). N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism. Nat Commun 12, 6314.
  26. Li, J., Zhang, H. & Wang, H. (2022). N(1)-methyladenosine modification in cancer biology: Current status and future perspectives. Comput Struct Biotechnol J 20, 6578-6585.
  27. Zheng, Q. et al. (2020). Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov 6, 12.
  28. Wu, Y. et al. (2022). RNA m(1)A methylation regulates glycolysis of cancer cells through modulating ATP5D. Proc Natl Acad Sci U S A 119, e2119038119.
  29. Chen, Z. et al. (2019). Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res 47, 2533-2545.
  30. Zhang, T. et al. (2022). RNA methylation regulators contribute to poor prognosis of hepatocellular carcinoma associated with the suppression of bile acid metabolism: a multi-omics analysis. Am J Cancer Res 12, 2989-3013
  31. Zhang, Y. et al. (2021). Alternative polyadenylation: methods, mechanism, function, and role in cancer. J Exp Clin Cancer Res 40, 51.
  32. Clerici, M., Faini, M., Muckenfuss, L. M., Aebersold, R. & Jinek, M. (2018). Structural basis of AAUAAA polyadenylation signal recognition by the human CPSF complex. Nat Struct Mol Biol 25, 135-138.
  33. Mayr, C. & Bartel, D. P. (2009). Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673-684.
  34. Malka, Y. et al. (2022). Alternative cleavage and polyadenylation generates downstream uncapped RNA isoforms with translation potential. Mol Cell 82, 3840-3855 e3848.
  35. Fischl, H. et al. (2019). hnRNPC regulates cancer-specific alternative cleavage and polyadenylation profiles. Nucleic Acids Res 47, 7580-7591.
  36. Ghosh, S. et al. (2022). CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis. Nucleic Acids Res 50, 3096-3114.
  37. Pieraccioli, M. et al. (2022). The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer. Nat Struct Mol Biol 29, 1101-1112.
  38. Kishor, A. et al. (2020). Activation and inhibition of nonsense-mediated mRNA decay control the abundance of alternative polyadenylation products. Nucleic Acids Res 48, 7468-7482.
  39. Li, N. et al. (2023). CFIm-mediated alternative polyadenylation safeguards the development of mammalian pre-implantation embryos. Stem Cell Reports 18, 81-96.
  40. Sommerkamp, P. & Trumpp, A. (2022). Driving differentiation: targeting APA in AML. Blood 139, 317-319.
  41. de Prisco, N. et al. (2023). Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites. Sci Adv 9, eade4814.
  42. Shandilya, J., Wang, Y. & Roberts, S. G. (2012). TFIIB dephosphorylation links transcription inhibition with the p53-dependent DNA damage response. Proc Natl Acad Sci U S A 109, 18797-18802.
  43. Brummer, A., Yang, Y., Chan, T. W. & Xiao, X. (2017). Structure-mediated modulation of mRNA abundance by A-to-I editing. Nat Commun 8, 1255.
  44. Yang, Y., Zhou, X. & Jin, Y. (2013). ADAR-mediated RNA editing in non-coding RNA sequences. Sci China Life Sci 56, 944-952.
  45. Kapoor, U. et al. (2020). ADAR-deficiency perturbs the global splicing landscape in mouse tissues. Genome Res 30, 1107-1118.
  46. Lyu, K. et al. (2022). An RNA G-Quadruplex Structure within the ADAR 5'UTR Interacts with DHX36 Helicase to Regulate Translation. Angew Chem Int Ed Engl 61, e202203553.
  47. de Reuver, R. et al. (2022). ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation. Nature 607, 784-789.
  48. Nishikura, K. (2010). Functions and regulation of RNA editing by ADAR deaminases. Annu Rev Biochem 79, 321-349.
  49. Nigita, G., Veneziano, D. & Ferro, A. (2015). A-to-I RNA Editing: Current Knowledge Sources and Computational Approaches with Special Emphasis on Non-Coding RNA Molecules. Front Bioeng Biotechnol 3, 37.
  50. Qi, L., Chan, T. H., Tenen, D. G. & Chen, L. (2014). RNA editome imbalance in hepatocellular carcinoma. Cancer Res 74, 1301-1306.
  51. Okugawa, Y., Grady, W. M. & Goel, A. (2015). Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 149, 1204-1225 e1212.
  52. Ni, W. et al. (2019). Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m(6)A reader YTHDF3. Mol Cancer 18, 143.
  53. Liu, Z. et al. (2022). Biological and pharmacological roles of m(6)A modifications in cancer drug resistance. Mol Cancer 21, 220.
  54. Zeng, D. et al. (2019). Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures. Cancer Immunol Res 7, 737-750.
  55. Jung, H. et al. (2019). DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load. Nat Commun 10, 4278.
  56. Rose, T. L. et al. (2021). Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience. Br J Cancer 125, 1251-1260.
  57. Yang, X. et al. (2020). METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer 19, 46.
  58. Ye, Y. et al. (2023). TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway. Eur J Med Res 28, 48.
  59. Nakano, M. et al. (2016). RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence. J Biol Chem 291, 894-903.
  60. Kang, H. J. et al. (2021). TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution. Nucleic Acids Res 49, 269-284.
  61. Braun, D. A. et al. (2020). Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med 26, 909-918.