Snail2 cooperates with Snail1 in the repression of vitamin D receptor in colon cancer.
Vitamin D receptor (VDR) mediates the antitumoral action of the active vitamin D metabolite 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)). VDR expression is lost during colon cancer progression causing unresponsiveness to 1,25(OH)(2)D(3) 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)(2)D(3). 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 p21(CIP1), filamin A and vinculin proteins and the repression of c-MYC by 1,25(OH)(2)D(3). Additionally, Snail2 abrogates beta-catenin nuclear export and the antagonism of the transcriptional activity of beta-catenin-T-cell factor complexes by 1,25(OH)(2)D(3). 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.
Larriba
María Jesús
MJ
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.
Martín-Villar
Ester
E
García
José Miguel
JM
Pereira
Fabio
F
Peña
Cristina
C
de Herreros
Antonio García
AG
Bonilla
Félix
F
Muñoz
Alberto
A
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D014807:Vitamin D / Q000031:analogs & derivatives / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D051153:Wnt Proteins; D051176:beta Catenin; C118756:dihydroxy-vitamin D3; D014807:Vitamin D