Pharmacologic disruption of Polycomb Repressive Complex 2 inhibits tumorigenicity and tumor progression in prostate cancer

Molecular Cancer

Research

Lesley A Mathews¹  Lei Sun¹  William L Farrar¹  Stephanie M Cabarcas¹  Francesco Crea¹  Victor E Marquez²  Romano Danesi³  Elaine M Hurt⁴ 

[1] Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA;Chemical Biology Laboratory, National Cancer Institute at Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA;Department of Internal Medicine, Division of Pharmacology, Pisa Medical School, Pisa, Italy;MedImmune, 20878, Gaithersburg, Maryland, USA;

关键词: Prostate Cancer;    Cancer Stem Cell;    LNCaP Cell;    DU145 Cell;    Prostate Cancer Progression;   

DOI  :  10.1186/1476-4598-10-40

 received in 2010-11-17, accepted in 2011-04-18,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundPolycomb repressive complex 2 (PRC2) mediates gene silencing through histone H3K27 methylation. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 3-Dezaneplanocin-A (DZNeP) is an inhibitor of PRC2 with broad anticancer activity.Methodwe investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145).ResultsExploring GEO and Oncomine databases, we found that specific PRC2 genes (EED, EZH2, SUZ12) predict poor prognosis in PC. Non-toxic DZNeP concentrations completely eradicated LNCaP and DU145 prostatosphere formation, and significantly reduced the expression of CSC markers. At comparable doses, other epigenetic drugs were not able to eradicate CSCs. DZNeP was also able to reduce PC cell invasion. Cells pre-treated with DZNeP were significantly less tumorigenic (LNCaP) and formed smaller tumors (DU145) in immunocompromised mice.ConclusionDZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.

【 授权许可】

Unknown   
© Crea et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.