Identification of the epigenetic reader CBX2 as a potential drug target in advanced prostate cancer

Pier-Luc Clermont,Dong Lin,Yuzhuo Wang,Wan L Lam,James Z L Wang,Yan Ting Chiang,Jiarui Ding,Rebecca Wu,Abhijit Parolia,Cheryl D Helgason,Colin C Collins,Hui Xue,Sohrab P Shah,Kelsie L Thu,Amy Zhang,Yuwei Wang,Francesco Crea

doi:10.1186/s13148-016-0182-9

Abstract

BackgroundWhile localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities.ResultsIn the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis.ConclusionsTaken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

Highlights

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC)
CBX2 is overexpressed in aggressive PCa As the first step to identify putative therapeutic targets for advanced PCa, we analyzed the expression of polycomb group (PcG) genes in the LTL313H/LTL313B patient-derived xenograft (PDX) model of metastatic and non-metastatic PCa [29]
This unique PDX pair recapitulates and exploits the intratumoral heterogeneity observed in clinical PCa as LTL313H consistently gives rises to metastases when implanted in the mouse subrenal capsule while LTL313B always stays local to the grafting site

Summary

Introduction

While localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities. While localized disease can be effectively treated with surgery or radiotherapy, metastatic PCa remains invariably fatal [2]. For the past 30 years, androgendeprivation therapy (ADT) has been the standard care for disseminated PCa. all tumors eventually acquire resistance to ADT and relapse in a highly aggressive state called castration-resistant prostate cancer (CRPC) [3]. Despite the introduction of novel therapeutic agents for late-stage patients, CRPC remains an Epigenetics refers to changes in transcriptional programs that cannot be attributed to modifications in DNA sequence [7]. Epigenetic mechanisms define gene expression programs which themselves specify

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