title: 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.
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.
authors.affiliation: Department of Medicine, University of California, Irvine, USA.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Sikandar
authors.affiliation: Department of Medicine, University of California, Irvine, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Dizon
authors.affiliation: Department of Biomedical Engineering, Cornell University, USA.
authors.forename: Xiling
authors.initials: X
authors.lastname: Shen
authors.affiliation: Methylgene, Quebec, Canada.
authors.forename: Zuomei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Methylgene, Quebec, Canada.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Besterman
authors.affiliation: Departments of Medicine and Genetic Medicine, Weill Cornell Medical College, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019073:HT29 Cells; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000145:classification / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D001549:Benzamides; C501126:DKK1 protein, human; D056572:Histone Deacetylase Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D011743:Pyrimidines; D051153:Wnt Proteins; C523184:mocetinostat