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

被引：130

作者：

Crea, Francesco ^{[1
]}

Hurt, Elaine M. ^{[2
]}

Mathews, Lesley A. ^{[1
]}

Cabarcas, Stephanie M. ^{[1
]}

Sun, Lei ^{[1
]}

Marquez, Victor E. ^{[3
]}

Danesi, Romano ^{[4
]}

Farrar, William L. ^{[1
]}

机构：

[1] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA

[2] Medimmune Inc, Gaithersburg, MD 20878 USA

[3] NCI, Biol Chem Lab, Ctr Canc Res, Frederick, MD 21701 USA

[4] Pisa Med Sch, Div Pharmacol, Dept Internal Med, Pisa, Italy

来源：

MOLECULAR CANCER | 2011年 / 10卷

基金：

美国国家卫生研究院;

关键词：

EPITHELIAL-MESENCHYMAL TRANSITION; GROUP PROTEIN EZH2; STEM-CELLS; E-CADHERIN; METASTASIS; GROWTH; ROLES; DNA;

D O I：

10.1186/1476-4598-10-40

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Background: Polycomb 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. Method: we investigated the effects of DZNeP on cell proliferation, tumorigenicity and invasive potential of PC cell lines (LNCaP and DU145). Results: Exploring 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. Conclusion: DZNeP is effective both in vitro and in vivo against PC cells. DZNeP antitumor activity is in part mediated by inhibition of CSC tumorigenic potential.

引用

页数：10

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