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.

  • Original Article
  • Published:

SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway

Oncogene volume 36, pages 2724–2736 (2017)Cite this article

Subjects

Abstract

SIRT4 is well-known for its deacetylase activity in energy metabolism, but little is known about its roles in carcinogenesis. We demonstrated that SIRT4 was decreased in 70 out of 133 non-small cell lung cancer (NSCLC) cases by immunohistochemical staining and localized in the mitochondria using confocal microscopy. Low levels of SIRT4 expression was correlated with tumor node metastasis (TNM) stage, histological type of tumor (adenocarcinoma), lymph nodal status, Ki-67 (proliferation index) and poor overall survival. We also studied the biological role of SIRT4 in lung cancer cell lines transfected with SIRT4 plasmid or SIRT4-siRNA. SIRT4 inhibited lung cancer cell proliferation, blocked the cell cycle and repressed cell invasion and migration. Mitochondrial dynamics has been implicated in malignant properties of cells, particularly metastasis that is the major cause of death in patients diagnosed with cancer including lung cancer. This is the first study to identify an association between SIRT4 expression and decreased mitochondrial fission, which was driven by Drp1. SIRT4 inhibited Drp1 phosphorylation and weakened Drp1 recruitment to the mitochondrial membrane via an interaction with Fis-1. SIRT4 expression was lower in nodal metastatic tumor samples than their corresponding primary tumors, and cases with low expression of SIRT4 tended to have high p-Drp1 labeling. Also, MEK/ERK activity appeared to be hampered by SIRT4 expression, which may have implications for cells’ invasive capacities. In conclusion, our findings suggest that SIRT4 functions as an important antitumor protein in NSCLC, and should be investigated further with respect to future anticancer strategies.

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin 2014; 64: 252–271.

    Article  PubMed  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A . Cancer statistics, 2015. CA Cancer J Clin 2015; 65: 5–29.

    Article  PubMed  Google Scholar 

  3. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A . Global cancer statistics, 2012. CA Cancer J Clin 2015; 65: 87–108.

    Article  PubMed  Google Scholar 

  4. Chambers AF, Groom AC, MacDonald IC . Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer 2002; 2: 563–572.

    Article  CAS  PubMed  Google Scholar 

  5. Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, Christodoulou DC, Murphy AJ et al. SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 2006; 126: 941–954.

    Article  CAS  PubMed  Google Scholar 

  6. Saunders LR, Verdin E . Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene 2007; 26: 5489–5504.

    Article  CAS  PubMed  Google Scholar 

  7. Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ, Castronovo V et al. Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J Biol Chem 2007; 282: 33583–33592.

    Article  CAS  PubMed  Google Scholar 

  8. Argmann C, Auwerx J . Insulin secretion: SIRT4 gets in on the act. Cell 2006; 126: 837–839.

    Article  CAS  PubMed  Google Scholar 

  9. Jeong SM, Xiao C, Finley LW, Lahusen T, Souza AL, Pierce K et al. SIRT4 has tumor-suppressive activity and regulates the cellular metabolic response to DNA damage by inhibiting mitochondrial glutamine metabolism. Cancer Cell 2013; 23: 450–463.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nasrin N, Wu X, Fortier E, Feng Y, Bare OC, Chen S et al. SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. J Biol Chem 2010; 285: 31995–32002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Csibi A, Fendt SM, Li C, Poulogiannis G, Choo AY, Chapski DJ et al. The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 2013; 153: 840–854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jeong SM, Lee A, Lee J, Haigis MC . SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem 2014; 289: 4135–4144.

    Article  CAS  PubMed  Google Scholar 

  13. Huang G, Cui F, Yu F, Lu H, Zhang M, Tang H et al. Sirtuin-4 (SIRT4) is downregulated and associated with some clinicopathological features in gastric adenocarcinoma. Biomed Pharmacother 2015; 72: 135–139.

    Article  CAS  PubMed  Google Scholar 

  14. Miyo M, Yamamoto H, Konno M, Colvin H, Nishida N, Koseki J et al. Tumour-suppressive function of SIRT4 in human colorectal cancer. Br J Cancer 2015; 113: 492–499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Antico Arciuch VG, Elguero ME, Poderoso JJ, Carreras MC . Mitochondrial regulation of cell cycle and proliferation. Antioxid Redox Signal 2012; 16: 1150–1180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chan DC . Mitochondrial fusion and fission in mammals. Annu Rev Cell Dev Biol 2006; 22: 79–99.

    Article  CAS  PubMed  Google Scholar 

  17. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW et al. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 2013; 32: 4814–4824.

    Article  CAS  PubMed  Google Scholar 

  18. Boland ML, Chourasia AH, Macleod KF . Mitochondrial dysfunction in cancer. Front Oncol 2013; 3: 292.

    Article  PubMed  PubMed Central  Google Scholar 

  19. van der Bliek AM, Shen Q, Kawajiri S . Mechanisms of mitochondrial fission and fusion. Cold Spring Harbor Perspect BIol 2013; 5: a011072.

    Article  Google Scholar 

  20. Westermann B . Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 2010; 11: 872–884.

    Article  CAS  PubMed  Google Scholar 

  21. Archer SL . Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 2013; 369: 2236–2251.

    Article  CAS  PubMed  Google Scholar 

  22. Grandemange S, Herzig S, Martinou JC . Mitochondrial dynamics and cancer. Semin Cancer Biol 2009; 19: 50–56.

    Article  CAS  PubMed  Google Scholar 

  23. Roberts ER, Thomas KJ . The role of mitochondria in the development and progression of lung cancer. Comput Struct Biotechnol J 2013; 6: e201303019.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Lennon FE, Salgia R . Mitochondrial dynamics: biology and therapy in lung cancer. Expert Opin Invest Drugs 2014; 23: 675–692.

    Article  CAS  Google Scholar 

  25. Rehman J, Zhang HJ, Toth PT, Zhang Y, Marsboom G, Hong Z et al. Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer. FASEB J 2012; 26: 2175–2186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thomas KJ, Jacobson MR . Defects in mitochondrial fission protein dynamin-related protein 1 are linked to apoptotic resistance and autophagy in a lung cancer model. PloS One 2012; 7: e45319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang Y, Dong QZ, Fu L, Stoecker M, Wang E, Wang EH . Overexpression of CRKL correlates with poor prognosis and cell proliferation in non-small cell lung cancer. Mol Carcinogenes 2013; 52: 890–899.

    Article  CAS  Google Scholar 

  28. Laurent G, German NJ, Saha AK, de Boer VC, Davies M, Koves TR et al. SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. Mol Cell 2013; 50: 686–698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Carafa V, Nebbioso A, Altucci L . Sirtuins and disease: the road ahead. Front Pharmacol 2012; 3: 4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pal AD, Basak NP, Banerjee AS, Banerjee S . Epstein-Barr virus latent membrane protein-2 A alters mitochondrial dynamics promoting cellular migration mediated by Notch signaling pathway. Carcinogenesis 2014; 35: 1592–1601.

    Article  CAS  PubMed  Google Scholar 

  31. Wan YY, Zhang JF, Yang ZJ, Jiang LP, Wei YF, Lai QN et al. Involvement of Drp1 in hypoxia-induced migration of human glioblastoma U251 cells. Oncol Rep 2014; 32: 619–626.

    Article  PubMed  Google Scholar 

  32. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K . Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 2007; 282: 11521–11529.

    Article  CAS  PubMed  Google Scholar 

  33. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C, Kuwana T et al. Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 2008; 14: 193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin F, Chengyao X, Qingchang L, Qianze D, Enhua W, Yan W . CRKL promotes lung cancer cell invasion through ERK-MMP9 pathway. Mol Carcinog 2015; 54: E35–E44.

    Article  PubMed  Google Scholar 

  35. Sebolt-Leopold JS, Herrera R . Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer 2004; 4: 937–947.

    Article  CAS  PubMed  Google Scholar 

  36. Webb CP, Van Aelst L, Wigler MH, Vande Woude GF . Signaling pathways in Ras-mediated tumorigenicity and metastasis. Proc Natl Acad Sci USA 1998; 95: 8773–8778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL et al. Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 2015; 57: 537–551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL et al. Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 2015; 57: 521–536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The study was supported by the National Natural Science Foundation of China (No. 81672964 to Qingchang Li and No. 81302022 to Qianze Dong).

Author information

Authors and Affiliations

  1. China medical university and Department of Pathology, College of Basic Medical Sciences, the First Affiliated Hospital of China Medical University Shenyang, Liaoning, China

    L Fu, Q Dong, J He, X Wang, J Xing, E Wang, X Qiu & Q Li

Authors
  1. L Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Q Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. X Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Xing
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. X Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Q Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Q Li.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fu, L., Dong, Q., He, J. et al. SIRT4 inhibits malignancy progression of NSCLCs, through mitochondrial dynamics mediated by the ERK-Drp1 pathway. Oncogene 36, 2724–2736 (2017). https://doi.org/10.1038/onc.2016.425

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2016.425

This article is cited by

Search

Advanced search

Quick links