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Tumor Biology

, Volume 37, Issue 8, pp 11409–11420 | Cite as

Higher EZH2 expression is associated with extramedullary infiltration in acute myeloid leukemia

  • Qiuhua Zhu
  • Lingxiu Zhang
  • Xiaodong Li
  • Fang Chen
  • Ling Jiang
  • Guopan Yu
  • Zhixiang Wang
  • Changxin Yin
  • Xuejie Jiang
  • Qingxiu Zhong
  • Hongsheng Zhou
  • Bingjie Ding
  • Chunli Wang
  • Fanyi Meng
Original Article

Abstract

Accumulating evidence indicates that enhancer of zeste homolog 2 (EZH2) promotes the metastatic ability of solid tumors, but the role of EZH2 in extramedullary infiltration (EMI) in acute myeloid leukemia (AML) has not been thoroughly explored. In the present study, we investigated the possible association between EZH2 and EMI. We found that the messenger RNA (mRNA) and protein expression levels of EZH2 in AML patients were both significantly higher than in idiopathic thrombocytopenic purpura (ITP) patients. Furthermore, a positive correlation between EZH2 mRNA expression and percentage of peripheral blood blasts wa s found in AML patients (r = 0.404, p = 0.009). The migratory capacities of Kasumi-1 and HL-60, which both show a high level of EZH2 expression, were markedly higher than those of U937 and KG-1α. In contrast, silencing of EZH2 resulted in reduction in proliferation and migration ability and an increase in apoptosis. The latter observation was accompanied by reduced expression of associated proteins p-ERK, p-cmyc, and matrix metalloproteinase 2 (MMP-2) and an increase in epithelial cadherin (E-cadherin). These data suggest that higher expression of EZH2 may be associated with extramedullary infiltration in acute myeloid leukemia and affect pathogenesis via activation of the p-ERK/p-cmyc/MMP-2 and E-cadherin signaling pathways.

Keywords

Acute myeloid leukemia EZH2 Extramedullary infiltration p-ERK/p-cmyc/MMP-2 

Notes

Authors’ contributions

Fanyi Meng, Qiuhua Zhu, and Lingxiu Zhang conceptualized and designed the study, collected and analyzed data, and drafted the paper; Qiuhua Zhu and Lingxiu Zhang performed the experiments. Qiuhua Zhu and Lingxiu Zhang contributed equally to this work. Fanyi Meng and Hongsheng Zhou helped to revise the paper. All authors read and approved the final manuscript.

Funding

This work was supported by Guangzhou Science and Technology Plan Projects (No. 2013J4100109) and the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20124433110001). National Natural Science Foundation of China (No. 81500138), Natural Science Foundation of Guangdong Province, China (No. 2014A030313270), Medical Research Foundation of Guangdong Province, China (No. B2014250).

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Hiçsönmez G, Çetin M, Tuncer AM, Yenicesu İ, Aslan D, Özyürek E, et al. Children with acute myeloblastic leukemia presenting with extramedullary infiltration: the effects of high-dose steroid treatment. Leukemia Res. 2004;28:25–34.CrossRefGoogle Scholar
  2. 2.
    Rege K, Swansbury GJ, Atra AA, Horton C, Min T, Dainton MG, et al. Disease features in acute myeloid leukemia with t(8;21)(q22;q22). Influence of age, secondary karyotype abnormalities, CD19 status, and extramedullary leukemia on survival. Leuk Lymphoma. 2000;40:67–77.CrossRefPubMedGoogle Scholar
  3. 3.
    Chang H, Brandwein J, Yi Q, Chun K, Patterson B, Brien B. Extramedullary infiltrates of AML are associated with CD56 expression, 11q23 abnormalities and inferior clinical outcome. Leukemia Res. 2004;28:1007–11.CrossRefGoogle Scholar
  4. 4.
    Kobayashi R, Tawa A, Hanada R, Horibe K, Tsuchida M, Tsukimoto I. Extramedullary infiltration at diagnosis and prognosis in children with acute myelogenous leukemia. Pediatr Blood Cancer. 2007;48:393–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Byrd JC, Weiss RB, Arthur DC, Lawrence D, Baer MR, Davey F, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol. 1997;15:466–75.CrossRefPubMedGoogle Scholar
  6. 6.
    Tanaka S, Miyagi S, Sashida G, Chiba T, Yuan J, Mochizuki-Kashio M, et al. EZH2 augments leukemogenicity by reinforcing differentiation blockage in acute myeloid leukemia. Blood. 2012;120:1107–17.CrossRefPubMedGoogle Scholar
  7. 7.
    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.CrossRefPubMedGoogle Scholar
  8. 8.
    Kim SH, Yang WI, Min YH, Ko YH, Yoon SO. The role of the polycomb repressive complex pathway in T and NK cell lymphoma: biological and prognostic implications. Tumor Biol. 2015.Google Scholar
  9. 9.
    Xiaojing Yang RKMK, Miller PBOT: CDKN1C(p57KIP2) is a direct target of EZH2 and suppressed by multiple epigenetic mechanisms in breast cancer cellsGoogle Scholar
  10. 10.
    Nakagawa S, Okabe H, Sakamoto Y, Hayashi H, Hashimoto D, Yokoyama N, et al. Enhancer of zeste homolog 2 (EZH2) promotes progression of cholangiocarcinoma cells by regulating cell cycle and apoptosis. Ann Surg Oncol. 2013;20:667–75.CrossRefGoogle Scholar
  11. 11.
    Seward S, Semaan A, Qazi AM, Gruzdyn OV, Chamala S, Bryant CC, et al. EZH2 blockade by RNA interference inhibits growth of ovarian cancer by facilitating re-expression of p21waf1/cip1 and by inhibiting mutant p53. Cancer Lett. 2013;336:53–60.CrossRefPubMedGoogle Scholar
  12. 12.
    Plath K, Fang J, Mlynarczyk-Evans SK, Cao R, Worringer KA, Wang H, et al. Role of histone H3 lysine 27 methylation in X inactivation. Science. 2003;300:131–5.CrossRefPubMedGoogle Scholar
  13. 13.
    Visser HP, Gunster MJ, Kluin-Nelemans HC, Manders EM, Raaphorst FM, Meijer CJ, et al. The Polycomb group protein EZH2 is upregulated in proliferating, cultured human mantle cell lymphoma. Br J Haematol. 2001;112:950–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Yamada A, Fujii S, Daiko H, Nishimura M, Chiba T, Ochiai A. Aberrant expression of EZH2 is associated with a poor outcome and P53 alteration in squamous cell carcinoma of the esophagus. Int J Oncol. 2011;38:345–53.PubMedGoogle Scholar
  15. 15.
    Cao W, Ribeiro RO, 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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, et al. Loss of let-7 up-regulates EZH2 in prostate cancer consistent with the acquisition of cancer stem cell signatures that are attenuated by BR-DIM. Plos One. 2012;7:e33729.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Tiwari N, Tiwari VK, Waldmeier L, Balwierz PJ, Arnold P, Pachkov M, et al. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling EZH2 expression and epigenetic reprogramming. Cancer Cell. 2013;23:768–83.CrossRefPubMedGoogle Scholar
  18. 18.
    Xu F, Li X, Wu L, Zhang Q, Yang R, Yang Y, et al. Overexpression of the EZH2, RING1 and BMI1 genes is common in myelodysplastic syndromes: relation to adverse epigenetic alteration and poor prognostic scoring. Ann Hematol. 2011;90:643–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Wu SH, Zheng CP, Xu J. A preliminary study on the relationship between EZH2 and microRNA-101 and the prognostic role of EZH2 in acute myeloid leukemia. Zhonghua Xue Ye Xue Za Zhi. 2012;33:232–5.PubMedGoogle Scholar
  20. 20.
    Jiang L, Yu G, Meng W, Wang Z, Meng F, Ma W. Overexpression of amyloid precursor protein in acute myeloid leukemia enhances extramedullary infiltration by MMP-2. Tumor Biol. 2013;34:629–36.CrossRefGoogle Scholar
  21. 21.
    Lin Y, Ren L, Xiong H, Du W, Yu Y, Sun T, et al. Role of STAT3 and vitamin D receptor inEZH2-mediated invasion of human colorectal cancer. J Pathol. 2013;230:277–90.CrossRefPubMedGoogle Scholar
  22. 22.
    Wang C, Chen Z, Li Z, Cen J. The essential roles of matrix metalloproteinase-2, membrane type 1 metalloproteinase and tissue inhibitor of metalloproteinase-2 in the invasive capacity of acute monocytic leukemia SHI-1 cells. Leukemia Res. 2010;34:1083–90.CrossRefGoogle Scholar
  23. 23.
    Shin YJ, Kim J. The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells. Plos One. 2012;7:e30393.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin a and the histone deacetylase inhibitor panobinostat against human AML cells. Blood. 2009;114:2733–43.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Liu L, Xu Z, Zhong L, Wang H, Jiang S, Long Q, et al. Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int. 2015;117(2):351–62.CrossRefPubMedGoogle Scholar
  26. 26.
    Lee SCW, Phipson B, Hyland CD, Leong HS, Allan RS, Lun A, et al. Polycomb repressive complex 2 (PRC2) suppresses E-myc lymphoma. Blood. 2013;122:2654–63.CrossRefPubMedGoogle Scholar
  27. 27.
    Grubach L, Juhl-Christensen C, Rethmeier A, Olesen LH, Aggerholm A, Hokland P, et al. Gene expression profiling of Polycomb, Hox and Meis genes in patients with acute myeloid leukaemia. Eur J Haematol. 2008;81:112–22.CrossRefPubMedGoogle Scholar
  28. 28.
    Chen J, Li J, Han Q, Sun Z, Wang J, Wang S, et al. Enhancer of zeste homolog 2 is overexpressed and contributes to epigenetic inactivation of p21 and phosphatase and tensin homolog in B-cell acute lymphoblastic leukemia. Exp Biol Med. 2012;237:1110–6.CrossRefGoogle Scholar
  29. 29.
    Nishioka C, Ikezoe T, Yang J, Yokoyama A. Tetraspanin family member, CD82, regulates expression of EZH2 via inactivation of p38 MAPK signaling in leukemia cells. Plos One. 2015;10:e125017.CrossRefGoogle Scholar
  30. 30.
    Zhou J, Bi C, Cheong LL, Mahara S, Liu SC, Tay KG, et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood. 2011;118:2830–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Fiskus W, Pranpat M, Balasis M, Herger B, Rao R, Chinnaiyan A, et al. Histone deacetylase inhibitors deplete enhancer of zeste 2 and associated polycomb repressive complex 2 proteins in human acute leukemia cells. Mol Cancer Ther. 2006;5:3096–104.CrossRefPubMedGoogle Scholar
  32. 32.
    Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Green R, et al. Silencing of human polycomb target genes is associated with methylation of histone H3 Lys 27. Genes Dev. 2004;18:1592–605.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Janowska-Wieczorek A, Marquez LA, Matsuzaki A, Hashmi HR, Larratt LM, Boshkov LM, et al. Expression of matrix metalloproteinases (MMP-2 and -9) and tissue inhibitors of metalloproteinases (TIMP-1 and -2) in acute myelogenous leukaemia blasts: comparison with normal bone marrow cells. Br J Haematol. 1999;105:402–11.CrossRefPubMedGoogle Scholar
  34. 34.
    Yasuda T. MAP kinase cascades in antigen receptor signaling and physiology. Curr Top Microbiol Immunol. 2015;393:211–31.Google Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Qiuhua Zhu
    • 1
  • Lingxiu Zhang
    • 1
  • Xiaodong Li
    • 1
  • Fang Chen
    • 1
  • Ling Jiang
    • 1
  • Guopan Yu
    • 1
  • Zhixiang Wang
    • 1
  • Changxin Yin
    • 1
  • Xuejie Jiang
    • 1
  • Qingxiu Zhong
    • 1
  • Hongsheng Zhou
    • 1
  • Bingjie Ding
    • 1
  • Chunli Wang
    • 1
  • Fanyi Meng
    • 1
    • 2
  1. 1.Department of Hematology, Nanfang HospitalSouthern Medical UniversityGuangzhouChina
  2. 2.Hematopathy Diagnosis and Therapy Center, Kanghua HospitalDongguanChina

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