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

Francesco Crea1, Elaine M Hurt, Lesley A Mathews

  • 1Cancer Stem Cell Section, Laboratory of Cancer Prevention, National Cancer Institute at Frederick, Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.

Molecular Cancer
|April 20, 2011
PubMed
Abstract

Insights

3-Deazaneplanocin-A (DZNeP) effectively targets prostate cancer (PC) by inhibiting Polycomb repressive complex 2 (PRC2). This epigenetic drug eradicates cancer stem cells (CSCs) and reduces tumor growth and invasion in preclinical models.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Stem Cell Biology

Background:

  • Polycomb repressive complex 2 (PRC2) regulates gene silencing via histone H3K27 methylation.
  • PRC2 components are overexpressed in metastatic prostate cancer (PC) and are crucial for cancer stem cell (CSC) self-renewal.
  • 3-Deazaneplanocin-A (DZNeP) is a PRC2 inhibitor with demonstrated anticancer properties.

Purpose of the Study:

  • To investigate the effects of DZNeP on prostate cancer cell proliferation, tumorigenicity, and invasiveness.
  • To evaluate DZNeP's efficacy in eradicating CSCs and its impact on CSC marker expression.
  • To assess DZNeP's in vivo antitumor activity in preclinical PC models.

Main Methods:

  • Analysis of PRC2 gene expression in PC patient data (GEO, Oncomine).
  • In vitro assessment of DZNeP's effects on PC cell lines (LNCaP, DU145) including prostatosphere formation and CSC marker expression.
  • In vivo studies using immunocompromised mice to evaluate DZNeP's impact on tumor growth and tumorigenicity.

Main Results:

  • Elevated expression of PRC2 genes (EED, EZH2, SUZ12) correlates with poor prognosis in PC.
  • DZNeP non-toxic concentrations eradicated CSC prostatosphere formation and reduced CSC marker expression, outperforming other epigenetic drugs.
  • DZNeP treatment significantly reduced PC cell invasion and inhibited tumor formation and growth in vivo.

Conclusions:

  • DZNeP exhibits significant in vitro and in vivo efficacy against prostate cancer cells.
  • The antitumor activity of DZNeP is partly attributed to its ability to inhibit CSC tumorigenic potential.
  • DZNeP represents a promising therapeutic agent for prostate cancer, particularly by targeting CSCs.

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