Differential effects of sulforaphane on histone deacetylases, cell cycle arrest and apoptosis in normal prostate cells versus hyperplastic and cancerous prostate cells

Mol Nutr Food Res. 2011 Jul;55(7):999-1009. doi: 10.1002/mnfr.201000547. Epub 2011 Mar 4.

Abstract

Scope: Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables such as broccoli. The ability of SFN to inhibit histone deacetylase (HDAC) enzymes may be one mechanism by which it acts as a chemoprevention agent. The ability of a chemopreventive agent to specifically cause cytotoxicity in cancer and not normal cells is an important factor in determining its safety and clinical relevance.

Methods and results: We characterized the effects of SFN in normal (PrEC), benign hyperplasia (BPH1) and cancerous (LnCap and PC3) prostate epithelial cells. We observed that 15 μM SFN selectively induced cell cycle arrest and apoptosis in BPH1, LnCap and PC3 cells but not PrEC cells. SFN treatment also selectively decreased HDAC activity, and Class I and II HDAC proteins, increased acetylated histone H3 at the promoter for P21, induced p21 expression and increased tubulin acetylation in prostate cancer cells. HDAC6 over-expression was able to reverse SFN-induced cyotoxicity. In PrEC cells, SFN caused only a transient reduction in HDAC activity with no change in any other endpoints tested. The differences in sensitivity to SFN in PrEC and PC3 are likely not due to differences in SFN metabolism or differences in phase 2 enzyme induction.

Conclusion: SFN exerts differential effects on cell proliferation, HDAC activity and downstream targets in normal and cancer cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Anticarcinogenic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Line
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Histone Deacetylase 2 / metabolism
  • Histone Deacetylase 6
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / drug effects*
  • Histone Deacetylases / metabolism
  • Histones / metabolism
  • Humans
  • Hyperplasia / drug therapy
  • Hyperplasia / pathology
  • Isothiocyanates
  • Male
  • NAD(P)H Dehydrogenase (Quinone) / drug effects
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • Promoter Regions, Genetic / drug effects
  • Prostate / cytology
  • Prostate / drug effects*
  • Prostate / pathology
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Thiocyanates / metabolism
  • Thiocyanates / pharmacology*
  • Tubulin / drug effects
  • Tubulin / metabolism

Substances

  • Anticarcinogenic Agents
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Histone Deacetylase Inhibitors
  • Histones
  • Isothiocyanates
  • Thiocyanates
  • Tubulin
  • NAD(P)H Dehydrogenase (Quinone)
  • NQO1 protein, human
  • HDAC2 protein, human
  • HDAC6 protein, human
  • Histone Deacetylase 2
  • Histone Deacetylase 6
  • Histone Deacetylases
  • histone deacetylase 3
  • sulforaphane