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The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer

Abstract

Several non-hypercalcemic analogs of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) show antitumor activity in a subset of cancer patients. High vitamin D receptor (VDR) expression, which is associated with good prognosis but is lost during tumor progression. We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)2D3 analog, in xenografted mice. In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR.

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Figure 1: SNAIL inhibits VDR expression and function in human SW480-ADH cells.
Figure 2: High SNAIL expression inhibits EB1089 antitumor action in vivo and correlates with VDR downregulation in human colon tumors.

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Acknowledgements

We thank L. Binderup for 1,25(OH)2D3 and EB1089, T. González for calcemia measurement and R. Rycroft for his help with the English manuscript. This study was supported by grants from Fundación Científica de la Asociación Española contra el Cáncer, Ministerio de Ciencia y Tecnología (SAF01-2291) and Instituto de Salud Carlos III (FIS03-C03/10) of Spain.

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Correspondence to Alberto Muñoz.

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Supplementary information

Supplementary Fig. 1

Sequence of the human VDR gene promoter. (PDF 102 kb)

Supplementary Fig. 2

Specificity of the repressive effective of SNAIL on human VDR gene promoter. (PDF 162 kb)

Supplementary Fig. 3

High SNAIL levels associate with E-cadherin repression in human colon cancer. (PDF 139 kb)

Supplementary Table 1

Inverse correlation between SNAIL and VDR expression in colon cancer. (PDF 179 kb)

Supplementary Table 2

Statistical analysis of the inverse relation between tumoral SNAIL RNA overexpression and the repression of VDR and E-cadherin expression. (PDF 85 kb)

Supplementary Methods (PDF 45 kb)

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Pálmer, H., Larriba, M., García, J. et al. The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. Nat Med 10, 917–919 (2004). https://doi.org/10.1038/nm1095

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