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

Pálmer, Héctor G.; Larriba, María Jesús; García, José M.; Ordóñez‐Morán, Paloma; Peña, Cristina; Peiró, Sandra; Puig, Isabel; Rodríguez, Rafael Gómez; Fuente, Ricardo de la; Bernad, António; Pollán, Marina; Bonilla, Félix; Gamallo, Carlos; Herreros, Antonio Garcı́a de; Múñoz, Alberto

doi:10.1038/nm1095

Cited by 258 publications

(252 citation statements)

References 11 publications

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“…CtBP1 then recruits HDAC1, and perhaps other effectors (e.g., HMT1), to catalyze histone modification and silencing of the VDR gene promoter. Although VDR gene promoter was shown to be regulated by other E2-box binding proteins in non-breast cells [14,15], ours is the first report of the direct involvement of SLUG in the modulation of the expression of VDR gene in human breast cells.…”

Section: In Vivo Binding Of Slug Ctbp1 and Hdac1 Proteins To The Vdrmentioning

confidence: 68%

In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells

Mittal

Myers

Misra

et al. 2008

Biochemical and Biophysical Research Communications

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The regulation of vitamin D receptor (VDR), a key mediator in the vitamin D pathway, in breast cancer etiology has long been of interest. We have shown here that the transcriptional repressor protein SLUG inhibits the expression of VDR in human breast cancer cells. To explore the possibility that SLUG regulates the VDR gene promoter, we cloned a 628 bp fragment (−613 to +15) of the human VDR gene promoter. This region contains three E2-box sequences (CAGGTG/CACCTG), the classical binding site of SLUG. SLUG specifically inhibited VDR gene promoter activity. Chromatin-immunoprecipitation (ChIP) assays revealed that SLUG is recruited on the native VDR gene promoter along with the co-repressor protein CtBP1 and the effector protein HDAC1. These data suggests that SLUG binds to the E2-box sequences of the VDR gene promoter and recruits CtBP1 and HDAC1, which results in the inhibition of VDR gene expression by chromatin remodeling. SLUG is a member of the SNAI family of C 2 H 2 -zinc finger family of transcriptional repressors [4][5][6]. It is involved in the epithelial-mesenchymal transition during development [5], acts as an inhibitor of apoptosis [7], and causes tubulogenesis during breast and kidney developments [4,5]. The genes inhibited by SLUG include E-cadherin [8], claudins [9], BRCA2 [10], and cytokeratins [11]. Our ChIP-DSL analysis of 20,000 human gene promoter array revealed that more than 150 promoters bind to SLUG at their promoters (Mittal, M.K. and Chaudhuri, G., unpublished data). VDR gene is one of the candidate SLUG-regulated genes. Here, we report that SLUG indeed binds in vivo to the VDR gene promoter in human breast cell nucleus and inhibits VDR gene expression by chromatin remodeling.

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Section: In Vivo Binding Of Slug Ctbp1 and Hdac1 Proteins To The Vdrmentioning

confidence: 68%

In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells

Mittal

Myers

Misra

et al. 2008

Biochemical and Biophysical Research Communications

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“…To ensure reproducibility, cultures were grown no longer than 3 months and monitored by PCR to prevent Mycoplasma contamination. The generation and properties of RWP-1, SW-480 or HT-29 M6 cells stably transfected with Snail1-HA have been described previously (Batlle et al, 2000;Pa´lmer et al, 2004;Peiro´et al, 2006). For generation of RWP-1 and RWP-1 Snail1-HA deficient in Akt2, cells were infected with lentivirus expressing shRNAs specific for Akt2 (from Sigma, TRCN 39968, 39969, 39970, 39971 and 39972), Akt1 (from Sigma, TRCN 39793,39794,39795,39796 and 39797) or the corresponding shRNA control .…”

Section: Methodsmentioning

confidence: 99%

“…A very similar effect on RNA levels was observed for Akt2 depletion on control or RWP1-Snail1 cells (Figure 7b). We also analyzed the repression of the vitamin D receptor (VDR), another direct target of Snail1 (Pa´lmer et al, 2004). Differently to control cells, Snail1 did not downregulate the VDR in Akt2-depleted cells (Figure 7a).…”

Section: Snail1 Repression Of Cdh1 Gene Expression Requires Akt2mentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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“…In contrast, vitamin D (1a,25-dihydroxyvitamin D 3 ) induces the expression of CDH1 and an epithelial phenotype in human colon cells expressing vitamin D receptor (VDR) (Palmer et al, 2001). In addition, we showed that SNAI1 represses VDR expression in tumor cell lines and that its gene expression in human tumors is associated with CDH1 and VDR downregulation (Palmer et al, 2004;Pena et al, 2005).…”

Section: Introductionmentioning

confidence: 94%

“…Amplification of SNA1P was thus avoided, which was checked by sequencing of the PCR fragments obtained. Primers used are shown in Supplementary Table 1. VDR, CDH1, and ZEB1 mRNA levels were calculated in the tumor and in normal adjacent and distant tissues by a relative quantification approach, in which the amounts in the targets were expressed in relation to the geometric average of three reference housekeeping genes: TATA binding protein, succinate dehydrogenase complex subunit A, and ubiquitin C (Palmer et al, 2004). The relative concentrations of target and reference genes were calculated by interpolation, using a standard curve of each gene generated with a serial dilution of a cDNA prepared from RNA extracted from SW480-ADH cells.…”

Section: Real-time Pcrmentioning

confidence: 99%

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

et al. 2009

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SNAI1, ZEB1, E-cadherin (CDH1), and vitamin D receptor (VDR) genes regulate the epithelial-mesenchymal transition (EMT) that initiates the invasion process of many tumor cells. We hypothesized that this process could also affect the behavior of normal cells adjacent to the tumor. To verify this hypothesis, the expression level of these genes was determined by quantitative RT-PCR in tumor, normal adjacent, and normal distant tissues from 32 colorectal cancer (CC) patients. In addition, we extended the study to human HaCaT normal keratinocytes and SW480-ADH colon cancer cells co-cultured with SW480-ADH cells overexpressing the mouse Snai1 gene. Of 18 CC cases with SNAI1 expression in tumor tissue, five also had SNAI1 in normal adjacent tissue (NAT). Expression of SNAI1 in tumor tissue correlated with downregulation of CDH1 and VDR genes in both tumor (P ¼ 0.047 and P ¼ 0.014, respectively) and NAT lacking SNAI1 expression (P ¼ 0.054 and P ¼ 0.003). ZEB1 expression was directly related to VDR expression in tumor tissue (r ¼ 0.39; P ¼ 0.027) and inversely to CDH1 in NAT (r ¼ À0.46; P ¼ 0.010). CDH1 and VDR were also downregulated in SW480-ADH and MaCaT cells, respectively, when they were co-cultured with Snai1-expressing cells. Furthermore, cytokine analysis showed differences in the conditioned media obtained from the two cell types. These results indicate that histologically normal tissue adjacent to tumor tissue expressing the EMT-inducing gene SNAI1 shows alterations in the expression of epithelial differentiation genes such as CDH1 and VDR.

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

Cited by 258 publications

References 11 publications

In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells

In vivo binding to and functional repression of the VDR gene promoter by SLUG in human breast cells

Akt2 interacts with Snail1 in the E-cadherin promoter

SNAI1 expression in colon cancer related with CDH1 and VDR downregulation in normal adjacent tissue

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