A Polycomb Repression Signature in Metastatic Prostate Cancer Predicts Cancer Outcome

Jindan Yu,Kenneth J Pienta,Rohit Mehra,Sooryanarayana Varambally,Xiaoju Wang,Arul M Chinnaiyan,Scott A Tomlins,Rajal B Shah,Guoan Chen,Xuhong Cao,Jianjun Yu,Debashis Ghosh,Daniel R Rhodes

doi:10.1158/0008-5472.can-07-2498

Abstract

The Polycomb Group (PcG) protein EZH2 is a critical component of a multiprotein complex that methylates Lys(27) of histone 3 (H3K27), which consequently leads to the repression of target gene expression. We have previously reported that EZH2 is overexpressed in metastatic prostate cancer and is a marker of aggressive diseases in clinically localized solid tumors. However, the global set of genes directly regulated by PcG in tumors is largely unknown, and thus how PcG mediates tumor progression remains unclear. Herein we mapped genome-wide H3K27 methylation in aggressive, disseminated human prostate cancer tissues. Integrative analysis revealed that a significant subset of these genes are also targets of PcG in embryonic stem cells, and their repression in tumors is associated with poor prognosis. By stepwise cross-validation, we developed a "Polycomb repression signature" composed of 14 direct targets of PcG in metastatic tumors. Notably, solid tumor subtypes in which this gene signature is repressed show poor clinical outcome in multiple microarray data sets of tumors including breast and prostate cancer. Taken together, our results show a fingerprint of PcG-mediated transcriptional repression in metastatic prostate cancer that is reminiscent of stem cells and associated with cancer progression. Therefore, PcG proteins play a central role in the epigenetic silencing of target genes and functionally link stem cells, metastasis, and cancer survival.

Highlights

Polycomb group (PcG) proteins are transcriptional repressors with important roles in preserving cellular identity
To investigate the mechanism of PcG proteins in regulating cancer progression, we mapped genomic sites occupied by Polycomb Repressive Complex 2 (PRC2) in late-stage, aggressive prostate cancer tissues by combining Chromatin immunoprecipitation (ChIP) with promoter arrays (Fig. 1)
By integrating genome-wide location data with cancer expression profiling data, we identified genes directly repressed by PRC2, termed ‘‘Polycomb repression signature’’, in cancer

Summary

Introduction

Polycomb group (PcG) proteins are transcriptional repressors with important roles in preserving cellular identity. The PcG proteins, EZH2 (enhancer of zeste 2), SUZ12 (suppressor of zeste 12), and EED (embryonic ectoderm development), form the Polycomb Repressive Complex 2 (PRC2) and trimethylate H3K27 on target gene promoters [1]. This histone mark is part of a preprogrammed cellular memory system that is inheritable through mitotic cell divisions and preserves cellular identity. We mapped PRC2 target genes in aggressive prostate tumors and investigated their association with cancer outcome

Experimental Procedures

Results

Discussion