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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.

Publication ,  Journal Article
Sikandar, S; Dizon, D; Shen, X; Li, Z; Besterman, J; Lipkin, SM
Published in: Oncotarget
November 2010

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.

Duke Scholars

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 2010

Volume

1

Issue

7

Start / End Page

596 / 605

Location

United States

Related Subject Headings

  • Wnt Proteins
  • Up-Regulation
  • Signal Transduction
  • Pyrimidines
  • Neoplastic Stem Cells
  • Mice
  • Intercellular Signaling Peptides and Proteins
  • Humans
  • Histone Deacetylase Inhibitors
  • Hela Cells
 

Citation

APA
Chicago
ICMJE
MLA
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Sikandar, S., Dizon, D., Shen, X., Li, Z., Besterman, J., & Lipkin, S. M. (2010). 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. Oncotarget, 1(7), 596–605. https://doi.org/10.18632/oncotarget.101001
Sikandar, Shaheen, Diana Dizon, Xiling Shen, Zuomei Li, Jeffery Besterman, and Steven M. Lipkin. “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.Oncotarget 1, no. 7 (November 2010): 596–605. https://doi.org/10.18632/oncotarget.101001.
Sikandar, Shaheen, et al. “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.Oncotarget, vol. 1, no. 7, Nov. 2010, pp. 596–605. Pubmed, doi:10.18632/oncotarget.101001.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

November 2010

Volume

1

Issue

7

Start / End Page

596 / 605

Location

United States

Related Subject Headings

  • Wnt Proteins
  • Up-Regulation
  • Signal Transduction
  • Pyrimidines
  • Neoplastic Stem Cells
  • Mice
  • Intercellular Signaling Peptides and Proteins
  • Humans
  • Histone Deacetylase Inhibitors
  • Hela Cells