Skip to main content

Advertisement

SpringerLink
Log in

c-myc-mediated upregulation of NAT10 facilitates tumor development via cell cycle regulation in non-small cell lung cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

N-acetyltransferase 10 (NAT10) is a nucleolar acetyltransferase and has been reported to facilitate tumorigenesis in various cancers, but its role in NSCLC and how it is regulated remain to be assessed. The expression of NAT10 was explored in online databases and our collected clinical specimens. The relationship of NAT10 and clinical characteristics was evaluated using the online databases. Functional analyses were utilized to determine the effect of NAT10 on the proliferation and migration abilities. KEGG pathway analyses were conducted to investigate NAT10-related pathways in NSCLC. The influence of NAT10 on cell cycle was assessed by flow cytometry and cell synchronization assay. The association between c-myc and NAT10 promoter was determined by ChIP. Compared with normal tissue, NAT10 was significantly overexpressed in NSCLC. Upregulated NAT10 was associated with more advanced stage for lung adenocarcinoma and shorter overall survival and first progression time for lung cancer. NAT10 could promote proliferation and migration of NSCLC cells in vitro. c-myc positively regulated the expression of NAT10 as a transcription factor. KEGG pathway analyses indicated that NAT10 was significantly involved in cell cycle regulation, cytokine–cytokine receptor interaction and other pathways. The knockdown of NAT10-induced G1 arrest, which was possibly mediated by the downregulation of cyclin D1.Our findings suggested that c-myc-mediated upregulation of NAT10 promoted the proliferation and migration of NSCLC cells and NAT10 might be a marker for prognosis and a promising target for treatment in NSCLC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

The data used in this study are available from the corresponding author upon reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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):209–49.

    Article  PubMed  Google Scholar 

  2. Thai AA, Solomon BJ, Sequist LV, Gainor JF, Heist RS. Lung cancer. Lancet. 2021;398(10299):535–54.

    Article  PubMed  Google Scholar 

  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  4. Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74–88.

    Article  CAS  PubMed  Google Scholar 

  5. Icard P, Fournel L, Wu Z, Alifano M, Lincet H. Interconnection between metabolism and cell cycle in cancer. Trends Biochem Sci. 2019;44(6):490–501.

    Article  CAS  PubMed  Google Scholar 

  6. Arango D, Sturgill D, Alhusaini N, Dillman AA, Sweet TJ, Hanson G, et al. Acetylation of cytidine in mRNA promotes translation efficiency. Cell. 2018;175(7):1872-1886.e24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fu D, Collins K. Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol Cell. 2007;28(5):773–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shen Q, Zheng X, McNutt MA, Guang L, Sun Y, Wang J, et al. NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules. Exp Cell Res. 2009;315(10):1653–67.

    Article  CAS  PubMed  Google Scholar 

  9. Liu X, Cai S, Zhang C, Liu Z, Luo J, Xing B, et al. Deacetylation of NAT10 by Sirt1 promotes the transition from rRNA biogenesis to autophagy upon energy stress. Nucleic Acids Res. 2018;46(18):9601–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Liu X, Tan Y, Zhang C, Zhang Y, Zhang L, Ren P, et al. NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2. EMBO Rep. 2016;17(3):349–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai S, Liu X, Zhang C, Xing B, Du X. Autoacetylation of NAT10 is critical for its function in rRNA transcription activation. Biochem Biophys Res Commun. 2017;483(1):624–9.

    Article  CAS  PubMed  Google Scholar 

  12. Liu HY, Liu YY, Yang F, Zhang L, Zhang FL, Hu X, et al. Acetylation of MORC2 by NAT10 regulates cell-cycle checkpoint control and resistance to DNA-damaging chemotherapy and radiotherapy in breast cancer. Nucleic Acids Res. 2020;48(7):3638–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang L, Li DQ. MORC2 regulates DNA damage response through a PARP1-dependent pathway. Nucleic Acids Res. 2019;47(16):8502–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zheng J, Tan Y, Liu X, Zhang C, Su K, Jiang Y, et al. NAT10 regulates mitotic cell fate by acetylating Eg5 to control bipolar spindle assembly and chromosome segregation. Cell Death Differ. 2022;29(4):846–60.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Jing Y, Wang Y, Tang J, Zhu X, Jin WL, et al. NAT10 promotes gastric cancer metastasis via N4-acetylated COL5A1. Signal Transduct Target Ther. 2021;6(1):173.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang H, Hou W, Wang HL, Liu HJ, Jia XY, Zheng XZ, et al. GSK-3β-regulated N-acetyltransferase 10 is involved in colorectal cancer invasion. Clin Cancer Res. 2014;20(17):4717–29.

    Article  CAS  PubMed  Google Scholar 

  17. Li Q, Liu X, Jin K, Lu M, Zhang C, Du X, et al. NAT10 is upregulated in hepatocellular carcinoma and enhances mutant p53 activity. BMC Cancer. 2017;17(1):605.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Tan Y, Zheng J, Liu X, Lu M, Zhang C, Xing B, et al. Loss of nucleolar localization of NAT10 promotes cell migration and invasion in hepatocellular carcinoma. Biochem Biophys Res Commun. 2018;499(4):1032–8.

    Article  CAS  PubMed  Google Scholar 

  19. Oh TI, Lee YM, Lim BO, Lim JH. Inhibition of NAT10 suppresses melanogenesis and melanoma growth by attenuating microphthalmia-associated transcription factor (MITF) expression. Int J Mol Sci. 2017. https://doi.org/10.3390/ijms18091924.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Wu J, Zhu H, Wu J, Chen W, Guan X. Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer. Am J Transl Res. 2018;10(1):256–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Liang P, Hu R, Liu Z, Miao M, Jiang H, Li C. NAT10 upregulation indicates a poor prognosis in acute myeloid leukemia. Curr Probl Cancer. 2020;44(2):100491.

    Article  PubMed  Google Scholar 

  22. Zi J, Han Q, Gu S, McGrath M, Kane S, Song C, et al. Targeting NAT10 induces apoptosis associated with enhancing endoplasmic reticulum stress in acute myeloid leukemia cells. Front Oncol. 2020;10:598107.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang X, Chen J, Jiang S, He S, Bai Y, Zhu L, et al. N-acetyltransferase 10 enhances doxorubicin resistance in human hepatocellular carcinoma cell lines by promoting the epithelial-to-mesenchymal transition. Oxid Med Cell Longev. 2019;2019:7561879.

    PubMed  PubMed Central  Google Scholar 

  24. Wu B, Chang N, Xi H, Xiong J, Zhou Y, Wu Y, et al. PHB2 promotes tumorigenesis via RACK1 in non-small cell lung cancer. Theranostics. 2021;11(7):3150–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wang J, Wang C, Xu P, Li X, Lu Y, Jin D, et al. PRMT1 is a novel molecular therapeutic target for clear cell renal cell carcinoma. Theranostics. 2021;11(11):5387–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhou L, Xu Q, Huang L, Jin J, Zuo X, Zhang Q, et al. Low-dose carboplatin reprograms tumor immune microenvironment through STING signaling pathway and synergizes with PD-1 inhibitors in lung cancer. Cancer Lett. 2021;500:163–71.

    Article  CAS  PubMed  Google Scholar 

  27. Booy EP, McRae EK, Koul A, Lin F, McKenna SA. The long non-coding RNA BC200 (BCYRN1) is critical for cancer cell survival and proliferation. Mol Cancer. 2017;16(1):109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Saleh-Gohari N, Helleday T. Conservative homologous recombination preferentially repairs DNA double-strand breaks in the S phase of the cell cycle in human cells. Nucleic Acids Res. 2004;32(12):3683–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Apraiz A, Mitxelena J, Zubiaga A. Studying cell cycle-regulated gene expression by two complementary cell synchronization protocols. J Vis Exp. 2017. https://doi.org/10.3791/55745.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Larrieu D, Britton S, Demir M, Rodriguez R, Jackson SP. Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science. 2014;344(6183):527–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov. 2015;5(10):1024–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. O’Connor MJ, Thakar T, Nicolae CM, Moldovan GL. PARP14 regulates cyclin D1 expression to promote cell-cycle progression. Oncogene. 2021;40(30):4872–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cao Y, Yao M, Wu Y, Ma N, Liu H, Zhang B. N-Acetyltransferase 10 promotes micronuclei formation to activate the senescence-associated secretory phenotype machinery in colorectal cancer cells. Transl Oncol. 2020;13(8): 100783.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Tao W, Tian G, Xu S, Li J, Zhang Z, Li J. NAT10 as a potential prognostic biomarker and therapeutic target for HNSCC. Cancer Cell Int. 2021;21(1):413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wu Y, Cao Y, Liu H, Yao M, Ma N, Zhang B. Remodelin, an inhibitor of NAT10, could suppress hypoxia-induced or constitutional expression of HIFs in cells. Mol Cell Biochem. 2020;472(1–2):19–31.

    Article  CAS  PubMed  Google Scholar 

  36. Suski JM, Braun M, Strmiska V, Sicinski P. Targeting cell-cycle machinery in cancer. Cancer Cell. 2021;39(6):759–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tchakarska G, Sola B. The double dealing of cyclin D1. Cell Cycle. 2020;19(2):163–78.

    Article  CAS  PubMed  Google Scholar 

  38. Liu H, Ling Y, Gong Y, Sun Y, Hou L, Zhang B. DNA damage induces N-acetyltransferase NAT10 gene expression through transcriptional activation. Mol Cell Biochem. 2007;300(1–2):249–58.

    Article  CAS  PubMed  Google Scholar 

  39. Jirawatnotai S, Hu Y, Livingston DM, Sicinski P. Proteomic identification of a direct role for cyclin d1 in DNA damage repair. Cancer Res. 2012;72(17):4289–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dong P, Maddali MV, Srimani JK, Thélot F, Nevins JR, Mathey-Prevot B, et al. Division of labour between Myc and G1 cyclins in cell cycle commitment and pace control. Nat Commun. 2014;5:4750.

    Article  CAS  PubMed  Google Scholar 

  41. Hermeking H, Rago C, Schuhmacher M, Li Q, Barrett JF, Obaya AJ, et al. Identification of CDK4 as a target of c-MYC. Proc Natl Acad Sci USA. 2000;97(5):2229–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Beier R, Bürgin A, Kiermaier A, Fero M, Karsunky H, Saffrich R, et al. Induction of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth by Myc are genetically separable events. Embo J. 2000;19(21):5813–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Bretones G, Delgado MD, León J. Myc and cell cycle control. Biochim Biophys Acta. 2015;1849(5):506–16.

    Article  CAS  PubMed  Google Scholar 

  44. Curti L, Campaner S. MYC-induced replicative stress: a double-edged sword for cancer development and treatment. Int J Mol Sci. 2021. https://doi.org/10.3390/ijms22126168.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was supported by grants from the National Natural Science Foundation of China (81770082) and the Natural Science Foundation of Jiangsu Province (BE2019719).

Author information

Author notes

  1. Zimu Wang and Yicong Huang contributed equally to this study.

Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, Jiangsu, China

    Zimu Wang, Wanjun Lu, Jiaxin Liu, Suhua Zhu, Hongbing Liu & Yong Song

  2. Donald Bren School of Information and Computer Sciences, University of California, Irvine, USA

    Yicong Huang

  3. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Nanjing University School of Medicine, Nanjing, 210008, Jiangsu, China

    Xinying Li

Authors
  1. Zimu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yicong Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wanjun Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiaxin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xinying Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Suhua Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hongbing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yong Song
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by ZW, YH, WL and JL. XL and SZ contributed to the interpretation of data. The first draft of the manuscript was written by ZW. HL and YS supervised the whole study. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hongbing Liu or Yong Song.

Ethics declarations

Conflict of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 158 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, Z., Huang, Y., Lu, W. et al. c-myc-mediated upregulation of NAT10 facilitates tumor development via cell cycle regulation in non-small cell lung cancer. Med Oncol 39, 140 (2022). https://doi.org/10.1007/s12032-022-01736-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-022-01736-6

Keywords

Search

Navigation