The transcription factors Snail1 and Snail2 repress vitamin D receptor during colon cancer progression

Abstract

Vitamin D receptor (VDR) mediates the antitumoral action of the active vitamin D metabolite 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3). However, VDR expression is lost during colon cancer progression, possibly causing unresponsiveness to 1,25(OH)2D3. Although several mechanisms responsible for resistance to 1,25(OH)2D3 action in different types of cancer had been reported, none explained the loss of VDR expression. We have found that the transcription factors Snail1 and Snail2, known as inducers of epithelial-to-mesenchymal transition (EMT), inhibit VDR expression and block 1,25(OH)2D3 action in colon cancer cells. Snail1 and Snail2 have an additive repressing effect on VDR gene promoter. These effects are specific to the Snail family, as other transcription factors that function as EMT inducers do not inhibit VDR expression in colon cancer cells. Moreover, we also found that the RNA expression of SNAI1 and SNAI2 is upregulated in human colorectal tumors and inversely correlates with that of VDR. Our results suggest that high levels of SNAIL1 and SNAIL2 are a probable cause of VDR downregulation and 1,25(OH)2D3 unresponsiveness in colon cancer. In addition, they may contribute to the improvement of protocols for the clinical use of vitamin D compounds, as they indicate that advanced colon cancer patients overexpressing SNAIL1 and SNAIL2 are not suitable candidates for this therapy.