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Molecular Diagnostics

m1A methylase TRMT6 promotes neuroblastoma development by demethylating SST mRNA in an m1A/YTHDF2-dependent manner

British Journal of Cancer volume 133, pages 1354–1364 (2025)Cite this article

Subjects

Abstract

Background

m1A, a prevalent RNA modification found in various RNA species, has recently been reported to modulate cancer progression. However, its effects on neuroblastoma remain uninvestigated.

Methods

The PCAT database was utilized to analyze the mRNA levels and survival probabilities of m1A regulator genes (TRMT6, TRMT61A, ALKBH1, and ALKBH3) in neuroblastoma patients. Silencing and recovery of TRMT6 were employed to investigate its role in neuroblastoma in vitro and in vivo. m1A-seq and RIP-qPCR were performed to identify and confirm the downstream targets of TRMT6. Additionally, Actinomycin D treatment was administered to assess mRNA stability.

Results

m1A transmethylase TRMT6 expression was significantly elevated in high-risk and late-stage neuroblastoma patients. Functionally, TRMT6 promotes the malignancy of neuroblastoma cells in vitro and promotes tumor growth and metastasis in vivo. Mechanistically, TRMT6 reduces SST mRNA levels by inhibiting its stability in an m1A-YTHDF2-dependent manner, thereby promoting the development of neuroblastoma. Furthermore, SST analog octreotide suppresses neuroblastoma cell malignancy, tumor growth, and metastasis.

Conclusions

TRMT6 mediates m1A modification of SST to promote neuroblastoma progression, suggesting that targeting TRMT6 may be a novel potential therapeutic approach for treating neuroblastoma.

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Fig. 1: TRMT6 is upregulated in late-stage neuroblastoma patients.
Fig. 2: TRMT6 promotes NB tumor growth and metastasis in vitro and in vivo.
Fig. 3: SST as an m1A modified target of TRMT6 in SK-N-BE cells.
Fig. 4: SST is a downstream target and negatively regulated by TRMT6 in NB.
Fig. 5: TRMT6 reduces SST mRNA level through decreasing its stability in an m1A-YTHDF2-dependent pathway.
Fig. 6: Octreotide significantly inhibits NB cell malignancy, tumor growth, and metastasis.

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Data availability

Data of the m1A-seq in this study have been deposited in the Gene Expression Omnibus (GEO) database under the accession number GSE297545. All data presented in this study are the available from the corresponding author upon request.

References

  1. Maris JM, Hogarty MD, Bagatell R, Cohn SL. Neuroblastoma. Lancet. 2007;369:2106–20.

    CAS  PubMed  Google Scholar 

  2. Smith EI, Haase GM, Seeger RC, Brodeur GM. A surgical perspective on the current staging in neuroblastoma-the International Neuroblastoma Staging System proposal. J Pediatr Surg. 1989;24:386–90.

    CAS  PubMed  Google Scholar 

  3. Cohn SL, Pearson AD, London WB, Monclair T, Ambros PF, Brodeur GM, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009;27:289–97.

    PubMed  PubMed Central  Google Scholar 

  4. Brodeur GM. Spontaneous regression of neuroblastoma. Cell Tissue Res. 2018;372:277–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Zafar A, Wang W, Liu G, Wang X, Xian W, McKeon F, et al. Molecular targeting therapies for neuroblastoma: progress and challenges. Med Res Rev. 2021;41:961–1021.

    PubMed  Google Scholar 

  6. Qiu B, Matthay KK. Advancing therapy for neuroblastoma. Nat Rev Clin Oncol. 2022;19:515–33.

    CAS  PubMed  Google Scholar 

  7. Fetahu IS, Taschner-Mandl S. Neuroblastoma and the epigenome. Cancer Metastasis Rev. 2021;40:173–89.

    PubMed  PubMed Central  Google Scholar 

  8. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, et al. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013;3:308–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Agris PF. The importance of being modified: roles of modified nucleosides and Mg2+ in RNA structure and function. Prog Nucleic Acid Res Mol Biol. 1996;53:79–129.

    CAS  PubMed  Google Scholar 

  10. Jin H, Huo C, Zhou T, Xie S. m(1)A RNA modification in gene expression regulation. Genes. 2022;13:910.

  11. Li J, Zhang H, Wang H. N(1)-methyladenosine modification in cancer biology: current status and future perspectives. Comput Struct Biotechnol J. 2022;20:6578–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang C, Jia G. Reversible RNA modification N(1)-methyladenosine (m(1)A) in mRNA and tRNA. Genom Proteom Bioinform. 2018;16:155–61.

    CAS  Google Scholar 

  13. Oerum S, Dégut C, Barraud P, Tisné C. m1A post-transcriptional modification in tRNAs. Biomolecules. 2017;7:20.

  14. Safra M, Sas-Chen A, Nir R, Winkler R, Nachshon A, Bar-Yaacov D, et al. The m1A landscape on cytosolic and mitochondrial mRNA at single-base resolution. Nature. 2017;551:251–5.

    CAS  PubMed  Google Scholar 

  15. Dominissini D, Nachtergaele S, Moshitch-Moshkovitz S, Peer E, Kol N, Ben-Haim MS, et al. The dynamic N(1)-methyladenosine methylome in eukaryotic messenger RNA. Nature. 2016;530:441–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Ozanick S, Krecic A, Andersland J, Anderson JT. The bipartite structure of the tRNA m1A58 methyltransferase from S. cerevisiae is conserved in humans. RNA. 2005;11:1281–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Li X, Xiong X, Zhang M, Wang K, Chen Y, Zhou J, et al. Base-resolution mapping reveals distinct m(1)A methylome in nuclear- and mitochondrial-encoded transcripts. Mol Cell. 2017;68:993–1005.e1009.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bar-Yaacov D, Frumkin I, Yashiro Y, Chujo T, Ishigami Y, Chemla Y, et al. Mitochondrial 16S rRNA Is Methylated by tRNA methyltransferase TRMT61B in All Vertebrates. PLoS Biol. 2016;14:e1002557.

    PubMed  PubMed Central  Google Scholar 

  19. Kuang W, Jin H, Yang F, Chen X, Liu J, Li T, et al. ALKBH3-dependent m(1)A demethylation of Aurora A mRNA inhibits ciliogenesis. Cell Discov. 2022;8:25.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu F, Clark W, Luo G, Wang X, Fu Y, Wei J, et al. ALKBH1-mediated tRNA demethylation regulates translation. Cell. 2016;167:816–828.e816.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang Y, Wang J, Li X, Xiong X, Wang J, Zhou Z, et al. N(1)-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism. Nat Commun. 2021;12:6314.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu Y, Zhou J, Li X, Zhang X, Shi J, Wang X, et al. tRNA-m(1)A modification promotes T cell expansion via efficient MYC protein synthesis. Nat Immunol. 2022;23:1433–44.

    CAS  PubMed  Google Scholar 

  23. Jiang C, Tian Y, Xu C, Zhang H, Gu L. Landscape of N1-methyladenosin (m1A) modification pattern in colorectal cancer. Cancer Rep. 2024;7:e1965.

    CAS  Google Scholar 

  24. Su Z, Monshaugen I, Wilson B, Wang F, Klungland A, Ougland R, et al. TRMT6/61A-dependent base methylation of tRNA-derived fragments regulates gene-silencing activity and the unfolded protein response in bladder cancer. Nat Commun. 2022;13:2165.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gu X, Zhuang A, Yu J, Yang L, Ge S, Ruan J, et al. Histone lactylation-boosted ALKBH3 potentiates tumor progression and diminished promyelocytic leukemia protein nuclear condensates by m1A demethylation of SP100A. Nucleic Acids Res. 2024;52:2273–89.

    CAS  PubMed  Google Scholar 

  26. Anderson J, Phan L, Cuesta R, Carlson BA, Pak M, Asano K, et al. The essential Gcd10p-Gcd14p nuclear complex is required for 1-methyladenosine modification and maturation of initiator methionyl-tRNA. Genes Dev. 1998;12:3650–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Monshaugen I, Luna L, Rhodes J, Kristiansen FIS, Lång A, Bøe SO, et al. Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer. Front Oncol. 2023;13:1334112.

    CAS  PubMed  Google Scholar 

  28. Wang Y, Huang Q, Deng T, Li BH, Ren XQ. Clinical significance of TRMT6 in hepatocellular carcinoma: a bioinformatics-based study. Med Sci Monit. 2019;25:3894–901.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Ye Y, Liu M, Wu F, Ou S, Wang W, Fei J, et al. TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway. Eur J Med Res. 2023;28:48.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang B, Niu L, Wang Z, Zhao Z. RNA m1A methyltransferase TRMT6 predicts poorer prognosis and promotes malignant behavior in glioma. Front Mol Biosci. 2021;8:692130.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Chang X, Zhu J, Hua RX, Deng C, Zhang J, Cheng J, et al. TRMT6 gene rs236110 C > A polymorphism increases the risk of Wilms tumor. Gene. 2023;882:147646.

    CAS  PubMed  Google Scholar 

  32. Miao L, Zhuo Z, Tang J, Huang X, Liu J, Wang HY, et al. FABP4 deactivates NF-κB-IL1α pathway by ubiquitinating ATPB in tumor-associated macrophages and promotes neuroblastoma progression. Clin Transl Med. 2021;11:e395.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    CAS  PubMed  Google Scholar 

  34. Meng J, Lu Z, Liu H, Zhang L, Zhang S, Chen Y, et al. A protocol for RNA methylation differential analysis with MeRIP-Seq data and exomePeak R/Bioconductor package. Methods. 2014;69:274–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Thorvaldsdóttir H, Robinson JT, Mesirov JP. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 2013;14:178–92.

    PubMed  Google Scholar 

  36. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell. 2012;149:1635–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    CAS  PubMed  Google Scholar 

  38. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    CAS  PubMed  Google Scholar 

  39. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Keene JD, Komisarow JM, Friedersdorf MB. RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts. Nat Protoc. 2006;1:302–7.

    CAS  PubMed  Google Scholar 

  41. Seo KW, Kleiner RE. YTHDF2 recognition of N(1)-methyladenosine (m(1)A)-modified RNA is associated with transcript destabilization. ACS Chem Biol. 2020;15:132–9.

    CAS  PubMed  Google Scholar 

  42. Zheng Q, Gan H, Yang F, Yao Y, Hao F, Hong L, et al. Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov. 2020;6:12.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Guan Q, Lin H, Hua W, Lin L, Liu J, Deng L, et al. Variant rs8400 enhances ALKBH5 expression through disrupting miR-186 binding and promotes neuroblastoma progression. Chin J Cancer Res. 2023;35:140–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun L, Coy DH. Somatostatin and its analogs. Curr Drug Targets. 2016;17:529–37.

    CAS  PubMed  Google Scholar 

  45. Reubi JC, Laissue JA. Multiple actions of somatostatin in neoplastic disease. Trends Pharm Sci. 1995;16:110–5.

    CAS  PubMed  Google Scholar 

  46. Cattaneo MG, Amoroso D, Gussoni G, Sanguini AM, Vicentini LM. A somatostatin analogue inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines. FEBS Lett. 1996;397:164–8.

    CAS  PubMed  Google Scholar 

  47. Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    CAS  PubMed  Google Scholar 

  48. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.

    PubMed  Google Scholar 

  49. Zeng H, Li M, Liu J, Zhu J, Cheng J, Li Y, et al. YTHDF2 gene rs3738067 A>G polymorphism decreases neuroblastoma risk in Chinese children: evidence from an eight-center case-control study. Front Med. 2021;8:797195.

    Google Scholar 

  50. Pomaville MM, He C. Advances in targeting RNA modifications for anticancer therapy. Trends Cancer. 2023;9:528–42.

  51. Li M, Ye J, Xia Y, Li M, Li G, Hu X, et al. METTL3 mediates chemoresistance by enhancing AML homing and engraftment via ITGA4. Leukemia. 2022;36:2586–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172:90–105.e123.

    CAS  PubMed  Google Scholar 

  53. Cattaneo MG, Scita G, Vicentini LM. Somatostatin inhibits PDGF-stimulated Ras activation in human neuroblastoma cells. FEBS Lett. 1999;459:64–68.

    CAS  PubMed  Google Scholar 

  54. Mercadante S, Porzio G. Octreotide for malignant bowel obstruction: twenty years after. Crit Rev Oncol Hematol. 2012;83:388–92.

    PubMed  Google Scholar 

  55. Graillon T, Romano D, Defilles C, Saveanu A, Mohamed A, Figarella-Branger D, et al. Octreotide therapy in meningiomas: in vitro study, clinical correlation, and literature review. J Neurosurg. 2017;127:660–9.

    CAS  PubMed  Google Scholar 

  56. Watson SA, Durrant LG, Morris DL. The effect of the E2 prostaglandin enprostil, and the somatostatin analogue SMS 201 995, on the growth of a human gastric cell line, MKN45G. Int J Cancer. 1990;45:90–94.

    CAS  PubMed  Google Scholar 

  57. Dy DY, Whitehead RH, Morris DL. SMS 201.995 inhibits in vitro and in vivo growth of human colon cancer. Cancer Res. 1992;52:917–23.

    CAS  PubMed  Google Scholar 

  58. Borgström P, Hassan M, Wassberg E, Refai E, Jonsson C, Larsson SA, et al. The somatostatin analogue octreotide inhibits neuroblastoma growth in vivo. Pediatr Res. 1999;46:328–32.

    PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (32300473,82002636, 82173593), Guangdong Basic and Applied Basic Research Foundation (2023A1515220053), the Science, Technology and Innovation Commission of Shenzhen (JCYJ20220531093213030).

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Author notes

  1. These authors contributed equally: Xinxin Zhang, Huiran Lin.

Authors and Affiliations

  1. Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China

    Xinxin Zhang, Huiran Lin, Huimin Yin, Yufeng Han, Liping Chen, Mengzhen Zhang, Jing He & Zhenjian Zhuo

  2. State Key Laboratory of Chemical Oncogenomics, Shenzhen Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, Guangdong, China

    Hongxia Chen & Zhenjian Zhuo

  3. Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China

    Hongxia Chen & Zhenjian Zhuo

  4. Brain Function and Disease Laboratory, Shantou University Medical College, Shantou, Guangdong, China

    Zhenjian Zhuo

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  1. Xinxin Zhang
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Contributions

Xinxin Zhang, Zhenjian Zhuo, and Jing He designed this project. Xinxin Zhang, Huimin Yin, Liping Chen, and Mengzhen Zhang completed the in vitro experiments. Xinxin Zhang, Huiran Lin, Huimin Yin, Yufeng Han, and Hongxia Chen conducted the in vivo experiments. Jing He collected NB samples and related clinical data. Xinxin Zhang provided the data analysis. Xinxin Zhang, Zhenjian Zhuo, and Jing He wrote the paper. All authors approved this version to be published.

Corresponding authors

Correspondence to Jing He or Zhenjian Zhuo.

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The authors declare no competing interests.

Ethics approval and consent to participate

All procedures involving neuroblastoma patients in this study were conducted following the standards of the Ethics Committee of Guangzhou Women and Children’s Medical Center (Approval number: 2023-120A01). Written consent was signed by patients’ guardians prior to sample collection.

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Zhang, X., Lin, H., Yin, H. et al. m1A methylase TRMT6 promotes neuroblastoma development by demethylating SST mRNA in an m1A/YTHDF2-dependent manner. Br J Cancer 133, 1354–1364 (2025). https://doi.org/10.1038/s41416-025-03152-9

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