Inhibition of PRC2 histone methyltransferase activity increases TRAIL-mediated apoptosis sensitivity in human colon cancer cells. Academic Article uri icon

Overview

MeSH

  • Adenosine
  • Cell Line, Tumor
  • DNA-Binding Proteins
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenomics
  • HT29 Cells
  • Humans
  • MCF-7 Cells
  • Promoter Regions, Genetic
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Tretinoin

MeSH Major

  • Apoptosis
  • Colonic Neoplasms
  • Histone-Lysine N-Methyltransferase
  • Polycomb Repressive Complex 2
  • TNF-Related Apoptosis-Inducing Ligand

abstract

  • Colorectal cancer is ranked among the top leading causes of cancer death in industrialized populations. Polycomb group proteins, including Suz12 and Ezh2, are epigenetic regulatory proteins that act as transcriptional repressors of many differentiation-associated genes and are overexpressed in a large subset of colorectal cancers. Retinoic acid (RA) acts as a negative regulator of PcG actions in stem cells, but has shown limited therapeutic potential in some solid tumors, including colorectal cancer, in part because of retinoic acid receptor β silencing. Through treatment with RA, Suz12 shRNA knockdown, or Ezh2 pharmacological inhibition with 3-deazaneplanocin A (DZNep), we increased TRAIL-mediated apoptosis in human colorectal cancer cell lines. This increased apoptosis in human colon cancer cells after RA or DZNep treatment was associated with a ~2.5-fold increase in TNFRSF10B (DR5) transcript levels and a 42% reduction in the H3K27me3 epigenetic mark at the TNFRSF10B promoter after DZNep addition. Taken together, our findings indicate that pharmacological inhibition of Polycomb repressive complex 2 histone methyltransferase activity may constitute a new epigenetic therapeutic strategy to overcome RA non-responsiveness in a subset of colorectal tumors by increasing TRAIL-mediated apoptosis sensitivity. Copyright © 2012 Wiley Periodicals, Inc.

publication date

  • April 2013

has subject area

  • Adenosine
  • Apoptosis
  • Cell Line, Tumor
  • Colonic Neoplasms
  • DNA-Binding Proteins
  • Enhancer of Zeste Homolog 2 Protein
  • Epigenomics
  • HT29 Cells
  • Histone-Lysine N-Methyltransferase
  • Humans
  • MCF-7 Cells
  • Polycomb Repressive Complex 2
  • Promoter Regions, Genetic
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • Tretinoin

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3947628

Digital Object Identifier (DOI)

  • 10.1002/jcp.24224

PubMed ID

  • 23001792

Additional Document Info

start page

  • 764

end page

  • 772

volume

  • 228

number

  • 4