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Carcinogenesis Advance Access originally published online on June 5, 2009
Carcinogenesis 2009 30(8):1459-1468; doi:10.1093/carcin/bgp140
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer

María Jesús Larriba1, Ester Martín-Villar1,4, José Miguel García2, Fabio Pereira1, Cristina Peña2,5, Antonio García de Herreros3, Félix Bonilla2 and Alberto Muñoz1,*

1 Department of Cancer Biology, Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain
2 Department of Medical Oncology, Hospital Universitario Puerta de Hierro Majadahonda, Joaquín Rodrigo 2, 28222 Majadahonda, Spain
3 Department of Cancer Research, IMIM-Hospital del Mar, Doctor Aiguader 88, 08003 Barcelona, Spain
4 Present address: Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 UL, UK
5 Present address: Department of Oncology and Pathology, Cancer Center Karolinska R8:03, Karolinska Institutet, SE-171 76 Stockholm, Sweden

* To whom correspondence should be addressed. Tel: +34 91 5854451; Fax: +34 91 5854401; Email: amunoz{at}iib.uam.es

Vitamin D receptor (VDR) mediates the antitumoral action of the active vitamin D metabolite 1{alpha},25-dihydroxyvitamin D3 (1,25(OH)2D3). VDR expression is lost during colon cancer progression causing unresponsiveness to 1,25(OH)2D3 and its analogs. Previously, Snail1, an inducer of epithelial-to-mesenchymal transition (EMT), was reported to inhibit VDR expression. Here, we show that Snail2/Slug, but not other EMT inducers such as Zeb1, Zeb2, E47 or Twist1, represses VDR gene promoter. Moreover, Snail2 and Snail1 show additive repressing effect on VDR promoter. Snail2 inhibits VDR RNA and protein and blocks the induction of E-cadherin and an adhesive phenotype by 1,25(OH)2D3. Snail2 reduces the ligand-induced VDR transcriptional activation of a consensus response element and of the CYP24 promoter. Concordantly, Snail2 inhibits the induction of CYP24 RNA and p21CIP1, filamin A and vinculin proteins and the repression of c-MYC by 1,25(OH)2D3. Additionally, Snail2 abrogates β-catenin nuclear export and the antagonism of the transcriptional activity of β-catenin–T-cell factor complexes by 1,25(OH)2D3. SNAI2 expression is upregulated in 58% of colorectal tumors and correlates inversely with that of VDR. However, VDR downregulation is higher in tumors coexpressing SNAI2 and SNAI1 than in those expressing only one of these genes. Together, these data indicate that Snail2 and Snail1 cooperate for VDR repression in colon cancer.

Abbreviations: EMT, epithelial-to-mesenchymal transition; GFP, green fluorescent protein; HA, hemagglutinin; IgG, immunoglobulin G; 1,25(OH)2D3, 1{alpha},25-dihydroxyvitamin D3; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; qRT–PCR, quantitative reverse transcription–polymerase chain reaction; SDHA, succinate dehydrogenase complex subunit A; TCF, T-cell factor; VDR, vitamin D receptor; VDRE, vitamin D response element

Received April 23, 2009; revised May 25, 2009; accepted May 26, 2009.


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