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

Clin Epigenetics. 2016 Feb 12;8:16. doi: 10.1186/s13148-016-0182-9. eCollection 2016.

Abstract

Background: 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.

Results: In 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.

Conclusions: Taken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.

Keywords: CBX2; Castration-resistant prostate cancer; Epigenetics; Metastatic prostate cancer; Polycomb.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Caspase 3 / metabolism
  • Epigenesis, Genetic / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Oligonucleotide Array Sequence Analysis
  • Polycomb Repressive Complex 1 / drug effects*
  • Polycomb Repressive Complex 1 / physiology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms, Castration-Resistant / drug therapy
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Tumor Cells, Cultured
  • Up-Regulation

Substances

  • CBX2 protein, human
  • Polycomb Repressive Complex 1
  • Caspase 3