title: DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3.
abstract: Aberrant activation of the Wnt/beta-catenin signaling pathway is a hallmark of colon cancer. We show that the Wnt antagonist DICKKOPF-4 (DKK-4) gene is repressed by 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) in human colon cancer cells. This effect correlated with the inhibition of the DKK-4 promoter. Chromatin immunoprecipitation assays revealed that 1,25(OH)2D3 induces early and transient binding of the vitamin D receptor (VDR) and the SMRT corepressor to the region adjacent to the transcription start site of DKK-4. Additionally, we demonstrate that the DKK-4 gene is a new downstream target of TCF/beta-catenin. Remarkably, expression of DKK-4 messenger RNA (mRNA) was not detected in a series of 29 human normal (N) colon biopsies but expression was upregulated in all the matched tumour (T) tissues. An inverse correlation existed between the expression of DKK-4 and VDR RNA in the Ts. Ectopic DKK-4 expression increased the migration and invasion properties of colon cancer cells and conditioned media (CM) from DKK-4-expressing cells enhanced the capacity to migrate and form capillary-like tubules of human primary microvascular endothelial cells. In conclusion, DKK-4 is upregulated in colon cancer and is associated with the acquisition of malignant properties by neoplastic cells. DKK-4 downregulation is a novel effect of 1,25(OH)2D3 that may contribute to its anticancer action.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Pendás-Franco
authors.forename: J M
authors.initials: JM
authors.lastname: García
authors.forename: C
authors.initials: C
authors.lastname: Peña
authors.forename: N
authors.initials: N
authors.lastname: Valle
authors.forename: H G
authors.initials: HG
authors.lastname: Pálmer
authors.forename: M
authors.initials: M
authors.lastname: Heinäniemi
authors.forename: C
authors.initials: C
authors.lastname: Carlberg
authors.forename: B
authors.initials: B
authors.lastname: Jiménez
authors.forename: F
authors.initials: F
authors.lastname: Bonilla
authors.forename: A
authors.initials: A
authors.lastname: Muñoz
authors.forename: J M
authors.initials: JM
authors.lastname: González-Sancho
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000209:etiology*; D011401:Promoter Regions, Genetic; D018167:Receptors, Calcitriol / Q000378:metabolism; D051820:TCF Transcription Factors / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*
chemical_list: C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D018167:Receptors, Calcitriol; D051820:TCF Transcription Factors; D051176:beta Catenin; D002117:Calcitriol