Skip to main content

Advertisement

SpringerLink
Log in

EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer

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

Abstract

Histone methylations play important roles in human cancer metastasis. Enhancer of zeste homolog 2 (EZH2) is a key component of the polycomb repressor complex 2, which is responsible for histone H3K27 methylation. EZH2 is overexpressed in lung cancer and epigenetically silences tumor suppressor genes. Here, we showed that EZH2 was up-regulated in lung cancer and had a positive correlation with pathologic stage, nodal involvement in lung cancer patients. Moreover, overexpression of EZH2 was correlated with reduced tissue inhibitor of metalloproteinase-3 (TIMP-3) expression, which was shown to be negatively associated with tumor metastasis. Of note, overall survival time of patients with high EZH2/low TIMP-3 expression was significantly shorter than that of patients with low EZH2/high TIMP-3 (P = 0.031). RNA interfering and pharmacologic inhibition of EZH2 reduced histone H3 lysine 27 tri-methylation level and increased TIMP-3 expression level. Knockdown of EZH2 by siRNA significantly reduced A549 cancer cell migration. In contrast, reduction of TIMP-3 in A549 cells partially rescued EZH2 deficiency-induced loss of cell migration capacity. Taken together, our findings indicate that EZH2 accelerates cancer cell migration, in part, via the repression of TIMP-3 expression, suggesting a potential mechanism by which EZH2 promotes lung cancer progression and metastasis.

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

Similar content being viewed by others

Abbreviations

NSCLC:

Non-small cell lung cancer

EZH2:

Enhancer of zeste homolog 2

PRC2:

Polycomb repressor complex 2

DZNep:

3-Deazanaplanocin A

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

H3K27me3:

H3 lysine 27 tri-methylation

TIMP-3:

Tissue inhibitor of metalloproteinase-3

IHC:

Immunohistochemistry

siNC:

siRNA negative control

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  Google Scholar 

  2. Travis WD. Pathology of lung cancer. Clin Chest Med. 2011;32:669–92.

    Article  PubMed  Google Scholar 

  3. Cao R, Wang L, Wang H, Xia L, Erdjument-Bromage H, Tempst P, et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science. 2002;298:1039–43.

    Article  CAS  PubMed  Google Scholar 

  4. Cao W, Ribeiro Rde O, Liu D, Saintigny P, Xia R, Xue Y, et al. EZH2 promotes malignant behaviors via cell cycle dysregulation and its mRNA level associates with prognosis of patient with non-small cell lung cancer. PLoS One. 2012;7:e52984.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Huqun, Ishikawa R, Zhang J, Miyazawa H, Goto Y, Shimizu Y, et al. Enhancer of zeste homolog 2 is a novel prognostic biomarker in nonsmall cell lung cancer. Cancer. 2012;118:1599–606.

    Article  CAS  PubMed  Google Scholar 

  6. Lv Y, Yuan C, Xiao X, Wang X, Ji X, Yu H, et al. The expression and significance of the enhancer of zeste homolog 2 in lung adenocarcinoma. Oncol Rep. 2012;28:147–54.

    CAS  PubMed  Google Scholar 

  7. Au SL, Wong CC, Lee JM, Wong CM, Ng IO. EZH2-mediated H3K27me3 is involved in epigenetic repression of deleted in liver cancer 1 in human cancers. PLoS One. 2013;8:e68226.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Chase A, Cross NC. Aberrations of EZH2 in cancer. Clin Cancer Res. 2011;17:2613–8.

    Article  CAS  PubMed  Google Scholar 

  9. Watanabe H, Soejima K, Yasuda H, Kawada I, Nakachi I, Yoda S, et al. Deregulation of histone lysine methyltransferases contributes to oncogenic transformation of human bronchoepithelial cells. Cancer Cell Int. 2008;8:15.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chetty C, Lakka SS, Bhoopathi P, Kunigal S, Geiss R, Rao JS. Tissue inhibitor of metalloproteinase 3 suppresses tumor angiogenesis in matrix metalloproteinase 2-down-regulated lung cancer. Cancer Res. 2008;68:4736–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003;92:827–39.

    Article  CAS  PubMed  Google Scholar 

  12. Mino N, Takenaka K, Sonobe M, Miyahara R, Yanagihara K, Otake Y, et al. Expression of tissue inhibitor of metalloproteinase-3 (TIMP-3) and its prognostic significance in resected non-small cell lung cancer. J Surg Oncol. 2007;95:250–7.

    Article  CAS  PubMed  Google Scholar 

  13. Yang H, Li J, Guo J, Zhang S. Expressions and significance of TIMP-3 and mtp53 in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2012;15:202–7.

    CAS  PubMed  Google Scholar 

  14. Shin YJ, Kim JH. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. PLoS One. 2012;7:e30393.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Yan J, Erdem H, Li R, Cai Y, Ayala G, Ittmann M, et al. Steroid receptor coactivator-3/AIB1 promotes cell migration and invasiveness through focal adhesion turnover and matrix metalloproteinase expression. Cancer Res. 2008;68:5460–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Stearman RS, Dwyer-Nield L, Zerbe L, Blaine SA, Chan Z, Bunn PA Jr, et al. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol. 2005;167:1763–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wang C, Liu X, Chen Z, Huang H, Jin Y, Kolokythas A, et al. Polycomb group protein EZH2-mediated E-cadherin repression promotes metastasis of oral tongue squamous cell carcinoma. Mol Carcinog. 2013;52:229–36.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Eskander RN, Ji T, Huynh B, Wardeh R, Randall LM, Hoang B. Inhibition of enhancer of zeste homolog 2 (EZH2) expression is associated with decreased tumor cell proliferation, migration, and invasion in endometrial cancer cell lines. Int J Gynecol Cancer. 2013;23:997–1005.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Anania MC, Sensi M, Radaelli E, Miranda C, Vizioli MG, Pagliardini S, et al. TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene. 2011;30:3011–23.

    Article  CAS  PubMed  Google Scholar 

  20. Klucky B, Mueller R, Vogt I, Teurich S, Hartenstein B, Breuhahn K, et al. Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion. Cancer Res. 2007;67:8198–206.

    Article  CAS  PubMed  Google Scholar 

  21. Ren G, Baritaki S, Marathe H, Feng J, Park S, Beach S, et al. Polycomb protein EZH2 regulates tumor invasion via the transcriptional repression of the metastasis suppressor RKIP in breast and prostate cancer. Cancer Res. 2012;72:3091–104.

    Article  CAS  PubMed  Google Scholar 

  22. Kikuchi J, Kinoshita I, Shimizu Y, Kikuchi E, Konishi J, Oizumi S, et al. Distinctive expression of the polycomb group proteins Bmi1 polycomb ring finger oncogene and enhancer of zeste homolog 2 in nonsmall cell lung cancers and their clinical and clinicopathologic significance. Cancer. 2010;116:3015–24.

    Article  CAS  PubMed  Google Scholar 

  23. Wan L, Li X, Shen H, Bai X. Quantitative analysis of EZH2 expression and its correlations with lung cancer patients’ clinical pathological characteristics. Clin Transl Oncol. 2013;15:132–8.

    Article  CAS  PubMed  Google Scholar 

  24. Yu J, Cao Q, Wu L, Dallol A, Li J, Chen G, et al. The neuronal repellent SLIT2 is a target for repression by EZH2 in prostate cancer. Oncogene. 2010;29:5370–80.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the Ministry of Science and Technology of the People’s Republic of China (2011CB944104 and 2010CB945101), the National Natural Science Foundation (81172009 and 81372168), Doctoral Fund of Ministry of Education of China (20110091120028), and Fundamental Research Funds for the Central Universities (090314340001), and a grant from “Twelve-Five Plan” the Major Program of Nanjing Medical Science and Technique Development Foundation (Molecular Mechanism Study on Metastasis and Clinical Efficacy Prediction of Non-small Cell Lung Cancer) and Third Level Training Program of Young Talent Project of Nanjing Health, Nanjing Medical Science and Technology Development Project (No. ZDX12013), and Young Professionals Foundation of Nanjing Chest Hospital.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, 210029, Jiangsu, China

    Chunhua Xu, Zhibo Hou, Ping Zhan, Jue Zou, Huidi Hu, Yuanqin Zhang & Like Yu

  2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing Biomedical Research Institute, Nanjing University, Nanjing, 210061, Jiangsu, China

    Wei Zhao, Cunjie Chang & Jun Yan

  3. Department of Respiratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, 210029, Jiangsu, China

    Xin Yao

Authors
  1. Chunhua Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhibo Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cunjie Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jue Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Huidi Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuanqin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xin Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Like Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jun Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Like Yu or Jun Yan.

Additional information

Chunhua Xu and Zhibo Hou equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, C., Hou, Z., Zhan, P. et al. EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer. Med Oncol 30, 713 (2013). https://doi.org/10.1007/s12032-013-0713-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-013-0713-6

Keywords

Search

Navigation