The class I HDAC inhibitor MGCD0103 induces cell cycle arrest and apoptosis in colon cancer initiating cells by upregulating Dickkopf-1 and non-canonical Wnt signaling. Academic Article uri icon

Overview

MeSH

  • Animals
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic
  • HT29 Cells
  • HeLa Cells
  • Histone Deacetylase Inhibitors
  • Humans
  • Mice
  • Signal Transduction
  • Up-Regulation

MeSH Major

  • Apoptosis
  • Benzamides
  • Carcinoma
  • Cell Cycle
  • Colonic Neoplasms
  • Intercellular Signaling Peptides and Proteins
  • Neoplastic Stem Cells
  • Pyrimidines
  • Wnt Proteins

abstract

  • Colorectal cancer metastatic recurrence and chemoresistance are major causes of morbidity and mortality. Colon cancer initiating cells (CCIC) are thought to contribute to both these processes. To identify drugs with anti-CCIC activity we screened a number of FDA approved and investigational compounds. We found that the class I selective histone deacetylase inhibitor (HDACi) MGCD0103 has significant activity against CCIC, and also significantly inhibits non-CCIC CRC cell xenograft formation. Both MGCD0103 and the pan-HDAC inhibitor Trichostatin impairs CCIC clonogenicity and cause cell cycle arrest and cell death. Gene expression profiling revealed that the canonical WNT ligand DKK-1 is a highly upregulated target of HDAC inhibitors. Despite the presence of APC mutations and constitutive WNT signaling in CCIC, both transfected and recombinant DKK-1 dramatically inhibit CCIC proliferation and clonogenicity. Overall, these data show that inhibition of class I HDACs is a promising novel approach to target both CCIC and non-CCIC CRC cells. Our studies also provide novel insights into roles for DKK1 in addition to canonical WNT signaling and the mechanism of CCIC tumor formation.

publication date

  • November 2010

has subject area

  • Animals
  • Apoptosis
  • Benzamides
  • Carcinoma
  • Cell Cycle
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Colonic Neoplasms
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic
  • HT29 Cells
  • HeLa Cells
  • Histone Deacetylase Inhibitors
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Neoplastic Stem Cells
  • Pyrimidines
  • Signal Transduction
  • Up-Regulation
  • Wnt Proteins

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3093052

PubMed ID

  • 21317455

Additional Document Info

start page

  • 596

end page

  • 605

volume

  • 1

number

  • 7