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

Francesco Crea,Victor E Marquez,William L Farrar,Romano Danesi,Elaine M Hurt,Lesley A Mathews,Stephanie M Cabarcas,Lei Sun

doi:10.1186/1476-4598-10-40

Abstract

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.

Highlights

Prostate cancer (PC) is the second leading cause of cancer death in men in the US [1]
Pc Progression is Associated with Prc2 Gene Overexpression To investigate the role of Polycomb repressive complex 2 (PRC2) gene silencing in prostate cancer (PC) progression, we queried the Oncomine database
We found that PRC2 target genes were down-regulated in metastatic and high N stage PC

Summary

Introduction

Prostate cancer (PC) is the second leading cause of cancer death in men in the US [1]. Disease confined to the prostate is curable, while metastatic PC is associated with poor prognosis. Endocrine therapy and docetaxel improve patient survival, metastatic disease eventually leads to death [2]. In the past few years, it has been determined that PC contains a cancer stem cell (CSC)-compartment [3]. This compartment shares with normal stem cells an unlimited potential for self-renewal and the ability to differentiate in many cell types. PRC2 components are over-expressed in metastatic prostate cancer (PC), and are required for cancer stem cell (CSC) self-renewal. 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

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Results

Conclusion