1. ¹Instituto de Investigaciones Biomedicas CSIC-UAM, Madrid, Spain
2. ²Department of Biochemistry, Universidad Autonoma de Madrid, Madrid, Spain
3. ³Cancer Research, London WC2A 3PX, UK
4. ⁴Project on Damage, Repair and Tissue Engineering CIEMAT, Madrid, Spain
5. ⁵Instituto de Biomedicina de Valencia CSIC, Valencia, Spain
6. ⁶Northwestern University Medical School, Department of Urology, Chicago, IL, USA

Correspondence: B Jimenez, Instituto de Investigaciones Biomedicas CSIC-UAM and Department of Biochemistry, Universidad Autonoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain. E-mail: bjimenez@iib.uam.es

Received 3 August 2004; Revised 1 April 2005; Accepted 29 April 2005; Published online 11 July 2005.

Abstract

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) has antitumor activity in addition to its classical action on calcium metabolism and bone tissue biology. It is thought to regulate the expression of multiple target genes and thus modulate processes critical for tumor growth and metastases. Here we show that 1,25(OH)₂D₃ differentially regulates the expression of Id1 and Id2 genes, members of a family of transcriptional regulators of cell proliferation and differentiation. 1,25(OH)₂D₃ induced epithelial differentiation in SW480-ADH human colon carcinoma cell line by promoting expression of the proteins implicated in adherent junction formation, including E-cadherin, and by inhibiting -catenin transcriptional activity. 1,25(OH)₂D₃ activated the human Id1 gene promoter and rapidly induced Id1 RNA and protein. Ectopic overexpression of Id1 was not sufficient to induce E-cadherin, which was critical for the morphological changes induced by 1,25(OH)₂D₃ in SW480-ADH cells. Conversely, Id2 transcription rate, RNA and protein levels were decreased by 1,25(OH)₂D₃. Id2 downregulation by 1,25(OH)₂D₃ mediated the antiproliferative effect of 1,25(OH)₂D₃ on SW480-ADH cells. In addition, we showed that 1,25(OH)₂D₃ changed the levels of the inducer of angiogenesis, vascular endothelial growth factor and the potent antiangiogenic factor thrombospondin-1, leading to a balanced change in the angiogenic potential of SW480-ADH human colon carcinoma cells.