Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

ACAT1-mediated METTL3 acetylation inhibits cell migration and invasion in triple negative breast cancer

Genes & Immunity volume 24, pages 99–107 (2023)Cite this article

Subjects

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive disease with poor prognosis. Acetylation modifications affect a great number of biological processes of malignant tumors. The current study aims at revealing the role of acetylation-related mechanism in TNBC progression. Methyltransferase like-3 (METTL3) was found to be downregulated in TNBC cells via quantitative polymerase chain reaction (qPCR) and western blot analyses. Co-Immunoprecipitation (Co-IP) and GST pulldown assays revealed the interaction between acetyl-CoA acetyltransferase 1 (ACAT1) and METTL3. Through further immunoprecipitation (IP) assay, we determined that ACAT1 stabilizes METTL3 protein via inhibiting the degradation of ubiquitin-proteasome. Functionally, ACAT1 inhibits TNBC cell migration and invasion. Moreover, nuclear receptor subfamily 2 group F member 6 (NR2F6) regulates ACAT1 expression at transcriptional level. Finally, we demonstrated that NR2F6/ACAT/METTL3 axis suppresses the migration and invasion of TNBC cells via METTL3. In conclusion, NR2F6 transcriptionally activates ACAT1 and promotes the suppressive effects of ACAT1-mediated METTL3 acetylation on TNBC cell migration and invasion.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: ACAT1 mediates the acetylation of METTL3.
Fig. 2: ACAT1 stabilizes METTL3 protein.
Fig. 3: ACAT1 suppresses cell migration and invasion in TNBC.
Fig. 4: NR2F6 regulates ACAT1 expression at the transcriptional level.
Fig. 5: NR2F6/ACAT1 axis suppresses the migration and invasion of TNBC cells.

Similar content being viewed by others

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol: Off J Am Soc Clin Oncol. 2013;31:3997–4013.

    Article  Google Scholar 

  2. Morris GJ, Naidu S, Topham AK, Guiles F, Xu Y, McCue P, et al. Differences in breast carcinoma characteristics in newly diagnosed African-American and Caucasian patients: a single-institution compilation compared with the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Cancer. 2007;110:876–84.

    Article  PubMed  Google Scholar 

  3. Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res: Off J Am Assoc Cancer Res. 2007;13:4429–34.

    Article  Google Scholar 

  4. Lin NU, Claus E, Sohl J, Razzak AR, Arnaout A, Winer EP. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer. 2008;113:2638–45.

    Article  PubMed  Google Scholar 

  5. Sukumar J, Gast K, Quiroga D, Lustberg M, Williams N. Triple-negative breast cancer: promising prognostic biomarkers currently in development. Expert Rev anticancer Ther. 2021;21:135–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wright HJ, Hou J, Xu B, Cortez M, Potma EO, Tromberg BJ, et al. CDCP1 drives triple-negative breast cancer metastasis through reduction of lipid-droplet abundance and stimulation of fatty acid oxidation. Proc Natl Acad Sci USA. 2017;114:E6556–e65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dong F, Ruan S, Wang J, Xia Y, Le K, Xiao X, et al. M2 macrophage-induced lncRNA PCAT6 facilitates tumorigenesis and angiogenesis of triple-negative breast cancer through modulation of VEGFR2. Cell Death Dis. 2020;11:728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shi Y, Zheng C, Jin Y, Bao B, Wang D, Hou K, et al. Reduced Expression of METTL3 Promotes Metastasis of Triple-Negative Breast Cancer by m6A Methylation-Mediated COL3A1 Up-Regulation. Front Oncol. 2020;10:1126.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Su X, Wellen KE, Rabinowitz JD. Metabolic control of methylation and acetylation. Curr Opin Chem Biol. 2016;30:52–60.

    Article  CAS  PubMed  Google Scholar 

  10. Di Cerbo V, Schneider R. Cancers with wrong HATs: the impact of acetylation. Brief Funct Genomics. 2013;12:231–43.

    Article  PubMed  Google Scholar 

  11. Hu H, Zhu W, Qin J, Chen M, Gong L, Li L, et al. Acetylation of PGK1 promotes liver cancer cell proliferation and tumorigenesis. Hepatol (Baltim, Md) 2017;65:515–28.

    Article  CAS  Google Scholar 

  12. Liu B, Wang T, Wang H, Zhang L, Xu F, Fang R, et al. Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer. J Hematol Oncol. 2018;11:26.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ni Y, Yang Y, Ran J, Zhang L, Yao M, Liu Z, et al. miR-15a-5p inhibits metastasis and lipid metabolism by suppressing histone acetylation in lung cancer. Free Radic Biol Med. 2020;161:150–62.

    Article  CAS  PubMed  Google Scholar 

  14. Senapati P, Kato H, Lee M, Leung A, Thai C, Sanchez A, et al. Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer. Epigenetics Chromatin. 2019;12:44.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Oba T, Ono M, Matoba H, Uehara T, Hasegawa Y, Ito KI. HDAC6 inhibition enhances the anti-tumor effect of eribulin through tubulin acetylation in triple-negative breast cancer cells. Breast Cancer Res Treat. 2021;186:37–51.

    Article  CAS  PubMed  Google Scholar 

  16. Li S, Wu H, Huang X, Jian Y, Kong L, Xu H, et al. BOP1 confers chemoresistance of triple-negative breast cancer by promoting CBP-mediated β-catenin acetylation. The. J Pathol. 2021;254:265–78.

    Article  CAS  PubMed  Google Scholar 

  17. Gu L, Zhu Y, Lin X, Tan X, Lu B, Li Y. Stabilization of FASN by ACAT1-mediated GNPAT acetylation promotes lipid metabolism and hepatocarcinogenesis. Oncogene. 2020;39:2437–49.

    Article  CAS  PubMed  Google Scholar 

  18. Zhu Y, Gu L, Lin X, Liu C, Lu B, Cui K, et al. Dynamic regulation of ME1 Phosphorylation and acetylation affects lipid metabolism and colorectal tumorigenesis. Mol Cell. 2020;77:138–49. e5.

    Article  CAS  PubMed  Google Scholar 

  19. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019;20:156–74.

    Article  CAS  PubMed  Google Scholar 

  20. Wu F, Chen W, Kang X, Jin L, Bai J, Zhang H, et al. A seven-nuclear receptor-based prognostic signature in breast cancer. Clin Transl Oncol: Off Publ Federation Span Oncol Soc Natl Cancer Inst Mex 2021;23:1292–303.

    Article  CAS  Google Scholar 

  21. Zhang J, Meng H, Zhang M, Zhang C, Huang M, Yan C, et al. Regulation of docetaxel chemosensitivity by NR2F6 in breast cancer. Endocr-Relat Cancer. 2020;27:309–23.

    Article  PubMed  Google Scholar 

  22. Wang H, Xu B, Shi J. N6-methyladenosine METTL3 promotes the breast cancer progression via targeting Bcl-2. Gene. 2020;722:144076.

    Article  CAS  PubMed  Google Scholar 

  23. Cai X, Wang X, Cao C, Gao Y, Zhang S, Yang Z, et al. HBXIP-elevated methyltransferase METTL3 promotes the progression of breast cancer via inhibiting tumor suppressor let-7g. Cancer Lett. 2018;415:11–9.

    Article  CAS  PubMed  Google Scholar 

  24. 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: Off J Balk Union Oncol. 2021;26:444–9.

    Google Scholar 

  25. Ye K, Wu Y, Sun Y, Lin J, Xu J. TLR4 siRNA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression. Life Sci. 2016;155:133–9.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We appreciate all the participants who provide support for the study.

Author information

Author notes

  1. These authors contributed equally: Gong Zhang, Ruyi Huang, Hui Zhao.

Authors and Affiliations

  1. Department of Thyroid and Breast Surgery, the Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, 211100, Jiangsu, China

    Gong Zhang, Hui Zhao, Yuke Xia, Hui Huang, Mengjia Qian, Yuehe Fu & Yiyao Cui

  2. The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, Jiangsu, China

    Ruyi Huang

Authors
  1. Gong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ruyi Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuke Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mengjia Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuehe Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yiyao Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GZ, RY, and HZ designed the research study. GZ, RY, HZ, YK, and HH performed the research and completed the figures. MJ and YH provided help and advice on the experiments. YY wrote the manuscript.

Corresponding author

Correspondence to Yiyao Cui.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, G., Huang, R., Zhao, H. et al. ACAT1-mediated METTL3 acetylation inhibits cell migration and invasion in triple negative breast cancer. Genes Immun 24, 99–107 (2023). https://doi.org/10.1038/s41435-023-00202-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41435-023-00202-1

This article is cited by

Search

Advanced search

Quick links