Tumor Biology

, Volume 36, Issue 7, pp 5341–5351 | Cite as

SUZ12 promotes gastric cancer cell proliferation and metastasis by regulating KLF2 and E-cadherin

  • Rui Xia
  • Fei-yan Jin
  • Kai Lu
  • Li Wan
  • Min Xie
  • Tong-peng Xu
  • Wei De
  • Zhao-xia Wang
Research Article


SUZ12 is a core component of the polycomb repressive complex 2 (PRC2), which could silence gene transcription by generating trimethylation on lysine 27 residue of histone H3 (H3K27Me3). Meanwhile, SUZ12 has been found to be overexpressed in multiple cancers; however, the clinical significance and molecular mechanisms of SUZ12 controlling gastric cancer cell proliferation and metastasis are unclear. In this study, we found that SUZ12 expression was significantly increased in 64 gastric tumor tissues compared with normal tissues. Additionally, SUZ12 expression was associated with pathological stage, metastasis distance, and shorter overall survival of gastric cancer patients. Knockdown of SUZ12 expression impaired cell proliferation and invasion in vitro, leading to the inhibition of metastasis in vivo. Upregulation of SUZ12 was found to play a key role in gastric cancer cell proliferation and metastasis through the regulation of EMT and KLF2 expression.


Gastric cancer SUZ12 Metastasis EMT KLF2 



This work was supported by grants from the National Natural Science Foundation of China (No. 81472198), the Key Clinical Medicine Technology Foundation of Jiangsu Province (No. BL2014096), and the Medical Key Talented Person Foundation of the Jiangsu Provincial Developing Health Project (No. RC2011080) to WZX

Conflicts of interest


Supplementary material

13277_2015_3195_MOESM1_ESM.xls (10 kb)
ESM 1 (XLS 9 kb)


  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. doi: 10.3322/caac.20073.CrossRefPubMedGoogle Scholar
  3. 3.
    Ali Z, Deng Y, Ma C. Progress of research in gastric cancer. J Nanosci Nanotechnol. 2012;12(11):8241–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet. 2007;8(4):286–98. doi: 10.1038/nrg2005.CrossRefPubMedGoogle Scholar
  5. 5.
    Simon JA, Kingston RE. Occupying chromatin: Polycomb mechanisms for getting to genomic targets, stopping transcriptional traffic, and staying put. Mol Cell. 2013;49(5):808–24. doi: 10.1016/j.molcel.2013.02.013.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Nagano T, Mitchell JA, Sanz LA, Pauler FM, Ferguson-Smith AC, Feil R, et al. The Air noncoding RNA epigenetically silences transcription by targeting G9a to chromatin. Science. 2008;322(5908):1717–20. doi: 10.1126/science.1163802.CrossRefPubMedGoogle Scholar
  7. 7.
    Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9. doi: 10.1038/nature09784.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Novak P, Jensen T, Oshiro MM, Wozniak RJ, Nouzova M, Watts GS, et al. Epigenetic inactivation of the HOXA gene cluster in breast cancer. Cancer Res. 2006;66(22):10664–70. doi: 10.1158/0008-5472.CAN-06-2761.CrossRefPubMedGoogle Scholar
  9. 9.
    Cao R, Zhang Y. SUZ12 is required for both the histone methyltransferase activity and the silencing function of the EED-EZH2 complex. Mol Cell. 2004;15(1):57–67. doi: 10.1016/j.molcel.2004.06.020.CrossRefPubMedGoogle Scholar
  10. 10.
    Li H, Ma X, Wang J, Koontz J, Nucci M, Sklar J. Effects of rearrangement and allelic exclusion of JJAZ1/SUZ12 on cell proliferation and survival. Proc Natl Acad Sci U S A. 2007;104(50):20001–6. doi: 10.1073/pnas.0709986104.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Li H, Cai Q, Wu H, Vathipadiekal V, Dobbin ZC, Li T, et al. SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK. Mol Cancer Res. 2012;10(11):1462–72. doi: 10.1158/1541-7786.MCR-12-0335.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Martin-Perez D, Sanchez E, Maestre L, Suela J, Vargiu P, Di Lisio L, et al. Deregulated expression of the polycomb-group protein SUZ12 target genes characterizes mantle cell lymphoma. Am J Pathol. 2010;177(2):930–42. doi: 10.2353/ajpath.2010.090769.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Liu C, Shi X, Wang L, Wu Y, Jin F, Bai C, et al. SUZ12 is involved in progression of non-small cell lung cancer by promoting cell proliferation and metastasis. Tumour Biol. 2014. doi: 10.1007/s13277-014-1804-5.Google Scholar
  14. 14.
    Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell. 2010;39(5):761–72. doi: 10.1016/j.molcel.2010.08.013.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    He LJ, Cai MY, Xu GL, Li JJ, Weng ZJ, Xu DZ, et al. Prognostic significance of overexpression of EZH2 and H3k27me3 proteins in gastric cancer. Asian Pac J Cancer Prev. 2012;13(7):3173–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Mattioli E, Vogiatzi P, Sun A, Abbadessa G, Angeloni G, D’Ugo D, et al. Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer. J Cell Physiol. 2007;210(1):183–91. doi: 10.1002/jcp.20833.CrossRefPubMedGoogle Scholar
  17. 17.
    Kilkenny C, Browne W, Cuthill IC, Emerson M, Altman DG. Animal research: reporting in vivo experiments: the ARRIVE guidelines. Br J Pharmacol. 2010;160(7):1577–9. doi: 10.1111/j.1476-5381.2010.00872.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Baylin SB, Ohm JE. Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer. 2006;6(2):107–16. doi: 10.1038/nrc1799.CrossRefPubMedGoogle Scholar
  19. 19.
    Hahn WC, Counter CM, Lundberg AS, Beijersbergen RL, Brooks MW, Weinberg RA. Creation of human tumour cells with defined genetic elements. Nature. 1999;400(6743):464–8. doi: 10.1038/22780.CrossRefPubMedGoogle Scholar
  20. 20.
    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21(2):163–7. doi: 10.1038/5947.CrossRefPubMedGoogle Scholar
  22. 22.
    Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer. 2004;4(2):143–53. doi: 10.1038/nrc1279.CrossRefPubMedGoogle Scholar
  23. 23.
    Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3(6):415–28. doi: 10.1038/nrg816.PubMedGoogle Scholar
  24. 24.
    Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6. doi: 10.1038/nature08975.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fan Y, Shen B, Tan M, Mu X, Qin Y, Zhang F, et al. TGF-beta-induced upregulation of malat1 promotes bladder cancer metastasis by associating with suz12. Clin Cancer Res. 2014;20(6):1531–41. doi: 10.1158/1078-0432.CCR-13-1455.CrossRefPubMedGoogle Scholar
  26. 26.
    Sato T, Kaneda A, Tsuji S, Isagawa T, Yamamoto S, Fujita T, et al. PRC2 overexpression and PRC2-target gene repression relating to poorer prognosis in small cell lung cancer. Sci Rep. 2013;3:1911. doi: 10.1038/srep01911.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Taniguchi H, Jacinto FV, Villanueva A, Fernandez AF, Yamamoto H, Carmona FJ, et al. Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer. Oncogene. 2012;31(15):1988–94. doi: 10.1038/onc.2011.387.CrossRefPubMedGoogle Scholar
  28. 28.
    Yin L, Wang JP, Xu TP, Chen WM, Huang MD, Xia R, et al. Downregulation of Kruppel-like factor 2 is associated with poor prognosis for nonsmall-cell lung cancer. Tumour Biol. 2014. doi: 10.1007/s13277-014-2943-4.Google Scholar
  29. 29.
    Herranz N, Pasini D, Diaz VM, Franci C, Gutierrez A, Dave N, et al. Polycomb complex 2 is required for E-cadherin repression by the Snail1 transcription factor. Mol Cell Biol. 2008;28(15):4772–81. doi: 10.1128/MCB. 00323-08.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Perl AK, Wilgenbus P, Dahl U, Semb H, Christofori G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature. 1998;392(6672):190–3. doi: 10.1038/32433.CrossRefPubMedGoogle Scholar
  31. 31.
    Kang Y, Massague J. Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004;118(3):277–9. doi: 10.1016/j.cell.2004.07.011.CrossRefPubMedGoogle Scholar
  32. 32.
    Bremnes RM, Veve R, Gabrielson E, Hirsch FR, Baron A, Bemis L, et al. High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer. J Clin Oncol. 2002;20(10):2417–28.CrossRefPubMedGoogle Scholar
  33. 33.
    Xing X, Tang YB, Yuan G, Wang Y, Wang J, Yang Y, et al. The prognostic value of E-cadherin in gastric cancer: a meta-analysis. Int J Cancer. 2013;132(11):2589–96. doi: 10.1002/ijc.27947.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyNanjing Medical UniversityNanjingChina
  2. 2.Department of General SurgeryThe Second Hospital of Liuanyung and Clinical Cancer Institute of LianyungangLianyungangChina
  3. 3.Department of Oncology, Second Affiliated HospitalNanjing Medical UniversityNanjingChina
  4. 4.Department of Oncology, First Affiliated HospitalNanjing Medical UniversityNanjingChina

Personalised recommendations