Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Prostate Cancer | Research article

Targeting Ezh2 could overcome docetaxel resistance in prostate cancer cells

Authors: Xiaofu Qiu, Wei Wang, Bijun Li, Bo Cheng, Kangjian Lin, Jian Bai, Huanhui Li, Guosheng Yang

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Docetaxel was used to treat metastatic CRPC patients. However, Doc resistance in prostate cancer (PCa) hinders its clinical application.

Objective

To understand the underlying mechanisms by which Doc resistance is developed and to find novel therapeutic target to cure Doc resistant PCa has clinical importance.

Methods

We established Doc resistant cell lines and explored the role of Ezh2 in the development of Doc resistance by overexpressing its cDNA or using its inhibitor.

Results

We found that Ezh2 was induced in our established Doc resistant (DocR) cells, which was attributable to the silenced expression of miR-101-3p and miR-138-5p. Blockage of Ezh2 activity by either inhibitor or miRNA mimics could overcome Doc resistance by suppressing Doc-induced cancer stem cells populations. Mechanistically, Ezh2 activity was required for the induced expression of Nanog, Sox2 and CD44 upon Doc treatment.

Conclusions

Targeting Ezh2 could overcome Doc resistance.
Appendix
Available only for authorised users
Literature
1.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRef
2.
Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276–308.CrossRef
3.
Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH, van der Kwast TH. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am J Pathol. 1994;144(4):735–46.PubMedPubMedCentral
4.
Knuuttila M, Yatkin E, Kallio J, Savolainen S, Laajala TD, Aittokallio T, Oksala R, Hakkinen M, Keski-Rahkonen P, Auriola S, et al. Castration induces up-regulation of intratumoral androgen biosynthesis and androgen receptor expression in an orthotopic VCaP human prostate cancer xenograft model. Am J Pathol. 2014;184(8):2163–73.CrossRef
5.
Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32(49):5501–11.CrossRef
6.
Hwang C. Overcoming docetaxel resistance in prostate cancer: a perspective review. Therapeutic advances in medical oncology. 2012;4(6):329–40.CrossRef
7.
Nakabayashi M, Sartor O, Jacobus S, Regan MM, McKearn D, Ross RW, Kantoff PW, Taplin ME, Oh WK. Response to docetaxel/carboplatin-based chemotherapy as first- and second-line therapy in patients with metastatic hormone-refractory prostate cancer. BJU Int. 2008;101(3):308–12.CrossRef
8.
Ramaswamy B, Puhalla S. Docetaxel: a tubulin-stabilizing agent approved for the management of several solid tumors. Drugs of today. 2006;42(4):265–79.CrossRef
9.
Fabbri F, Amadori D, Carloni S, Brigliadori G, Tesei A, Ulivi P, Rosetti M, Vannini I, Arienti C, Zoli W, et al. Mitotic catastrophe and apoptosis induced by docetaxel in hormone-refractory prostate cancer cells. J Cell Physiol. 2008;217(2):494–501.CrossRef
10.
Morse DL, Gray H, Payne CM, Gillies RJ. Docetaxel induces cell death through mitotic catastrophe in human breast cancer cells. Mol Cancer Ther. 2005;4(10):1495–504.CrossRef
11.
Colloca G, Venturino A, Checcaglini F. Second-line chemotherapy in metastatic docetaxel-resistant prostate cancer: a review. Med Oncol. 2012;29(2):776–85.CrossRef
12.
Reuter CW, Morgan MA, Ivanyi P, Fenner M, Ganser A, Grunwald V. Carboplatin plus weekly docetaxel as salvage chemotherapy in docetaxel-resistant and castration-resistant prostate cancer. World J Urol. 2010;28(3):391–8.CrossRef
13.
Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature. 2011;469(7330):343–9.CrossRef
14.
Kim KH, Roberts CW. Targeting EZH2 in cancer. Nat Med. 2016;22(2):128–34.CrossRef
15.
Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, Wu X, Stack EC, Loda M, Liu T, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338(6113):1465–9.CrossRef
16.
Yang YA, Yu J. EZH2, an epigenetic driver of prostate cancer. Protein & cell. 2013;4(5):331–41.CrossRef
17.
van Vlerken LE, Kiefer CM, Morehouse C, Li Y, Groves C, Wilson SD, Yao Y, Hollingsworth RE, Hurt EM. EZH2 is required for breast and pancreatic cancer stem cell maintenance and can be used as a functional cancer stem cell reporter. Stem Cells Transl Med. 2013;2(1):43–52.CrossRef
18.
Li K, Liu C, Zhou B, Bi L, Huang H, Lin T, Xu K. Role of EZH2 in the growth of prostate cancer stem cells isolated from LNCaP cells. Int J Mol Sci. 2013;14(6):11981–93.CrossRef
19.
Kong D, Heath E, Chen W, Cher ML, Powell I, Heilbrun L, Li Y, Ali S, Sethi S, Hassan O, 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(3):e33729.CrossRef
20.
Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N. Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 2010;70(20):7992–8002.CrossRef
21.
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, Vessella RL, Corey E, Nanus DM, Plymate SR, Giannakakou P. Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res. 2014;74(8):2270–82.CrossRef
22.
Zhu Y, Liu C, Nadiminty N, Lou W, Tummala R, Evans CP, Gao AC. Inhibition of ABCB1 expression overcomes acquired docetaxel resistance in prostate cancer. Mol Cancer Ther. 2013;12(9):1829–36.CrossRef
23.
Yoshino T, Shiina H, Urakami S, Kikuno N, Yoneda T, Shigeno K, Igawa M. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006;12(20 Pt 1):6116–24.CrossRef
24.
O'Neill AJ, Prencipe M, Dowling C, Fan Y, Mulrane L, Gallagher WM, O'Connor D, O'Connor R, Devery A, Corcoran C, et al. Characterisation and manipulation of docetaxel resistant prostate cancer cell lines. Mol Cancer. 2011;10:126.CrossRef
25.
Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R. Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev. 2006;20(5):515–24.CrossRef
26.
Cao P, Deng Z, Wan M, Huang W, Cramer SD, Xu J, Lei M, Sui G. MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1alpha/HIF-1beta. Mol Cancer. 2010;9:108.CrossRef
27.
Popovic R, Martinez-Garcia E, Giannopoulou EG, Zhang Q, Zhang Q, Ezponda T, Shah MY, Zheng Y, Will CM, Small EC, et al. Histone methyltransferase MMSET/NSD2 alters EZH2 binding and reprograms the myeloma epigenome through global and focal changes in H3K36 and H3K27 methylation. PLoS Genet. 2014;10(9):e1004566.CrossRef
28.
Asangani IA, Ateeq B, Cao Q, Dodson L, Pandhi M, Kunju LP, Mehra R, Lonigro RJ, Siddiqui J, Palanisamy N, et al. Characterization of the EZH2-MMSET histone methyltransferase regulatory axis in cancer. Mol Cell. 2013;49(1):80–93.CrossRef
Metadata
Title
Targeting Ezh2 could overcome docetaxel resistance in prostate cancer cells
Authors
Xiaofu Qiu
Wei Wang
Bijun Li
Bo Cheng
Kangjian Lin
Jian Bai
Huanhui Li
Guosheng Yang
Publication date
01-12-2019
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5228-2

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

Vitronectin as a molecular player of the tumor microenvironment in neuroblastoma

Research article

The imbalance in the complement system and its possible physiological mechanisms in patients with lung cancer

Research article

Geographic distribution and risk of upper urothelial carcinomas in Croatia, 2001–2011

Research article

The histone methyltransferase WHSC1 is regulated by EZH2 and is important for ovarian clear cell carcinoma cell proliferation

Research article

Mesenchymal stem cells promote glioma neovascularization in vivo by fusing with cancer stem cells

Research article

Association between TIMP-2 gene polymorphism and breast cancer in Han Chinese women
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits