Inhibition of Enhancer of Zeste Homolog 2 (EZH2) Expression is Associated with Decreased Tumor Cell Proliferation, Migration, and Invasion in Endometrial Cancer Cell Lines

Overview

Journal Int J Gynecol Cancer

Specialties Gynecology & Obstetrics
Oncology

Date 2013 Jun 25

PMID 23792601

Citations 37

Authors

Ramez N Eskander

Tao Ji

Be Huynh

Rooba Wardeh

Leslie M Randall

Bang Hoang

Affiliations

Soon will be listed here.

Abstract

Objective: To investigate the impact of enhancer of zeste homolog 2 (EZH2) expression on endometrial cancer cell line behavior.

Materials And Methods: Enhancer of zeste homolog 2 expression levels were compared between the nonmalignant endometrial cell line T-HESC and 3 endometrial cancer cell lines, ECC-1, RL95-2, and HEC1-A. Stable EZH2 knockdown cell lines were created, and the impact on cellular proliferation, migration, and invasion were determined. Fluorescent activated cell sorting was used to examine effects of EZH2 silencing on cell cycle progression. Enhancer of zeste homolog 2 expression in endometrial cancer tissue specimens was examined using immunohistochemistry. Comparison of differences between control and short-hairpin EZH2 cell lines was performed using the Student t test and the Fischer exact test.

Results: Enhancer of zeste homolog 2 protein expression was increased in all 3 cancer cell lines and human endometrial cancer tissue specimens relative to control. RNA interference of EZH2 expression in ECC-1, RL95-2, and HEC1-A significantly decreased cell proliferation, migration, and invasion. Down-regulation of EZH2 expression resulted in a significant increase in the proportion of cells arrested in the G2/M phase. RNA interference of EZH2 expression was associated with an increase in the expression of Wnt pathway inhibitors sFRP1 and DKK3 and a concomitant decrease in β-catenin. Enhancer of zeste homolog 2 expression in human tissue samples was significantly associated with increased stage, grade, depth of invasion, and nodal metastasis.

Conclusions: Enhancer of zeste homolog 2 expression is associated with tumor cell proliferation, migration, and invasion in 3 endometrial cancer cell lines as well as with increased stage, grade, depth of invasion, and nodal metastasis in human cancer tissue specimens. Further investigation into this potential therapeutic target is warranted.

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References

Zi X, Simoneau A . Flavokawain A, a novel chalcone from kava extract, induces apoptosis in bladder cancer cells by involvement of Bax protein-dependent and mitochondria-dependent apoptotic pathway and suppresses tumor growth in mice. Cancer Res. 2005; 65(8):3479-86. DOI: 10.1158/0008-5472.CAN-04-3803. View

Kretzner L, Scuto A, Dino P, Kowolik C, Wu J, Ventura P . Combining histone deacetylase inhibitor vorinostat with aurora kinase inhibitors enhances lymphoma cell killing with repression of c-Myc, hTERT, and microRNA levels. Cancer Res. 2011; 71(11):3912-20. PMC: 3107377. DOI: 10.1158/0008-5472.CAN-10-2259. View

Oza A, Elit L, Tsao M, Kamel-Reid S, Biagi J, Provencher D . Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011; 29(24):3278-85. PMC: 3158598. DOI: 10.1200/JCO.2010.34.1578. View

Siegel R, Naishadham D, Jemal A . Cancer statistics, 2012. CA Cancer J Clin. 2012; 62(1):10-29. DOI: 10.3322/caac.20138. View

Lane A, Chabner B . Histone deacetylase inhibitors in cancer therapy. J Clin Oncol. 2009; 27(32):5459-68. DOI: 10.1200/JCO.2009.22.1291. View

Aghajanian C, Sill M, Darcy K, Greer B, McMeekin D, Rose P . Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011; 29(16):2259-65. PMC: 3107744. DOI: 10.1200/JCO.2010.32.6397. View

Varambally S, Dhanasekaran S, Zhou M, Barrette T, Kumar-Sinha C, Sanda M . The polycomb group protein EZH2 is involved in progression of prostate cancer. Nature. 2002; 419(6907):624-9. DOI: 10.1038/nature01075. View

Bryant R, Cross N, Eaton C, Hamdy F, Cunliffe V . EZH2 promotes proliferation and invasiveness of prostate cancer cells. Prostate. 2007; 67(5):547-56. DOI: 10.1002/pros.20550. View

Dellinger T, Planutis K, Tewari K, Holcombe R . Role of canonical Wnt signaling in endometrial carcinogenesis. Expert Rev Anticancer Ther. 2011; 12(1):51-62. DOI: 10.1586/era.11.194. View

10.

Creasman W, BORONOW R, Morrow C, Disaia P, Blessing J . Adenocarcinoma of the endometrium: its metastatic lymph node potential. A preliminary report. Gynecol Oncol. 1976; 4(3):239-43. DOI: 10.1016/0090-8258(76)90028-7. View

11.

Zhou J, Roh J, Bandyopadhyay S, Chen Z, Munkarah A, Hussein Y . Overexpression of enhancer of zeste homolog 2 (EZH2) and focal adhesion kinase (FAK) in high grade endometrial carcinoma. Gynecol Oncol. 2012; 128(2):344-8. DOI: 10.1016/j.ygyno.2012.07.128. View

12.

Cao Q, Dhanasekaran S, Kim J, Mani R, Tomlins S, Mehra R . Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene. 2008; 27(58):7274-84. PMC: 2690514. DOI: 10.1038/onc.2008.333. View

13.

Bracken A, Pasini D, Capra M, Prosperini E, Colli E, Helin K . EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J. 2003; 22(20):5323-35. PMC: 213796. DOI: 10.1093/emboj/cdg542. View

14.

Hwang C, Huang H, Chen C, Chien C, Hsu Y, Li C . Enhancer of zeste homolog 2 overexpression in nasopharyngeal carcinoma: an independent poor prognosticator that enhances cell growth. Int J Radiat Oncol Biol Phys. 2011; 82(2):597-604. DOI: 10.1016/j.ijrobp.2010.11.062. View

15.

Marks P, Xu W . Histone deacetylase inhibitors: Potential in cancer therapy. J Cell Biochem. 2009; 107(4):600-8. PMC: 2766855. DOI: 10.1002/jcb.22185. View

16.

Banerjee R, Mani R, Russo N, Scanlon C, Tsodikov A, Jing X . The tumor suppressor gene rap1GAP is silenced by miR-101-mediated EZH2 overexpression in invasive squamous cell carcinoma. Oncogene. 2011; 30(42):4339-49. PMC: 3154567. DOI: 10.1038/onc.2011.141. View

17.

Dellinger T, Monk B . Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev Anticancer Ther. 2009; 9(7):905-16. DOI: 10.1586/era.09.54. View

18.

Kidani K, Osaki M, Tamura T, Yamaga K, Shomori K, Ryoke K . High expression of EZH2 is associated with tumor proliferation and prognosis in human oral squamous cell carcinomas. Oral Oncol. 2008; 45(1):39-46. DOI: 10.1016/j.oraloncology.2008.03.016. View

19.

Noble J, Bailey M . Quantitation of protein. Methods Enzymol. 2009; 463:73-95. DOI: 10.1016/S0076-6879(09)63008-1. View

20.

Kleer C, Cao Q, Varambally S, Shen R, Ota I, Tomlins S . EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells. Proc Natl Acad Sci U S A. 2003; 100(20):11606-11. PMC: 208805. DOI: 10.1073/pnas.1933744100. View