Vitamin D represses EMT in human colon cancer cells

Abstract

Resumen del trabajo presentado al "6th International EMT Meeting: Symposium VI. Cancer and EMT I" celebrado en Alicante (España) del 13 al 16 de noviembre de 2013.The active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (calcitriol, 1,25(OH)2D3) is a pleiotropic secosteroid hormone with wide regulatory actions. 1,25(OH)2D3 acts via the vitamin D receptor (VDR), a member of the superfamily of nuclear receptors, which binds specific DNA sequences in its target genes and modulates their transcription rate. Additionally, 1,25(OH)2D3 activates rapid, non-genomic signaling pathways. We have reported that 1,25(OH)2D3 inhibits proliferation and induces differentiation of human colon carcinoma cells via the control of a high number of genes and the antagonism of the Wnt/beta-catenin pathway (Pálmer et al., J. Cell Biol., 2001; Cancer Res., 2003). 1,25(OH)2D3 increases the expression of CDH1/E-cadherin RNA and protein through the activation of a rapid non-genomic pathway (Ca2+-RhoA-ROCK-MSK1) and the subsequent increase in transcription (Ordóñez-Morán et al., J. Cell Biol., 2008). Additionally, it induces other proteins involved in epithelial adhesion structures such as the tight junctions components claudin-7, occludin and ZO-1. These effects are partially mediated by the induction of CST5/cystatin D, a protease inhibitor that regulates gene expression within the cell nucleus, and KDM6B/JMJD3 histone H3 lysine 27 demethylase, and by the repression of SPROUTY-2, a modulator of tyrosine kinase receptor signalling (Alvarez-Díaz et al., J. Clin. Invest., 2009; Barbáchano et al., Oncogene, 2010; Pereira et al., Human Mol. Genet., 2011). In addition, CST5/cystatin D and KDM6B/JMJD3 downregulate SNAI1, SNAI2, ZEB1 and ZEB2 genes. Moreover, SPROUTY-2 represses miR-200b/c leading to ZEB1 upregulation, and also several adhesion and polarity genes and ESRP1, an inhibitor of EMT. Remarkably, a reciprocal inhibitory loop exists between 1,25(OH)2D3 and EMT, as SNAIL1 and SNAIL2/SLUG repress VDR expression (Pálmer et al., Nat. Med., 2004; Larriba et al., Carcinogenesis, 2009). Altogether, our results show that 1,25(OH)2D3 represses EMT in human colon carcinoma cells through several mechanisms that affect the expression of EMT regulators and of epithelial adhesion and polarity genes. Conversely, the EMT inducers SNAIL1/2 inactivate the vitamin D system via VDR downregulation.Peer Reviewe