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Regulation of the Tumor Suppressor Homeogene Cdx2 by Hnf4a in Intestinal Cancer

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Regulation of the Tumor Suppressor Homeogene Cdx2 by Hnf4a in Intestinal Cancer Oncogene (2013) 32, 3782–3788 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION Regulation of the tumor suppressor homeogene Cdx2 by HNF4a in intestinal cancer T Saandi1,2, F Baraille3,4,5, L Derbal-Wolfrom1,2, A-L Cattin3,4,5, F Benahmed1,6, E Martin1,2, P Cardot3,4,5, B Duclos1,2,7, A Ribeiro3,4,5, J-N Freund1,2,8 and I Duluc1,2,8 The gut-specific homeotic transcription factor Cdx2 is a crucial regulator of intestinal development and homeostasis, which is downregulated in colorectal cancers (CRC) and exhibits a tumor suppressor function in the colon. We have previously established that several endodermal transcription factors, including HNF4a and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4a in the mechanism of deregulation of Cdx2 in colon cancers. Crossing ApcD14/ þ mice prone to spontaneous intestinal tumor development with pCdx2-9LacZ transgenic mice containing the LacZ reporter under the control of the 9.3-kb Cdx2 promoter showed that this promoter segment contains sequences recapitulating the decrease of Cdx2 expression in intestinal cancers. Immunohistochemistry revealed that HNF4a, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apcmin/ þ and ApcD14/ þ ) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4a and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4a and Cdx2 in several experimental models of human colon cancer cell lines: xenografts in nude mice, wound healing and glucose starvation. Furthermore, Cdx2 decreased by knocking down HNF4a in human colon cancer cells using siRNA and in the colon of mice conditionally knocked out for the Hnf4a gene in the adult intestine (Hnf4af/f;VilCreERT2 mice). Finally, the conditionally knocked out mice Hnf4af/f;VilCreERT2 treated with the carcinogen AOM developed colorectal tumors earlier than wild-type mice, as previously reported for mice with a reduced Cdx2 expression. In conclusion, this study provides evidence that the downregulation of HNF4a is an important determinant of the reduced expression of the Cdx2 tumor suppressor gene in intestinal cancers. Consistently, similar to Cdx2, HNF4a exerts a tumor suppressor function in the colon in that its loss of function facilitates tumor progression. Oncogene (2013) 32, 3782–3788; doi:10.1038/onc.2012.401; published online 17 September 2012 Keywords: intestine; hepatocyte nuclear factor; tumor suppressor; homeobox gene INTRODUCTION transgenic and molecular approaches.13 The proximal promoter A complex network of genes contributes to the constant renewal is sufficient to recapitulate the pattern of Cdx2 during embryonic of the intestinal epithelium. Among them, the Cdx2 homeotic development; however, sustained and tissue-specific expression in gene is essential during development1 and homeostasis,2,3 as it the adult gut requires far upstream sequences. These include a controls the organization of the stem cell niche, provides intestinal phylogenetically conserved segment located about 8.5 kb up- identity to stem cells and participates in the cell-autono- stream of the Cdx2 transcription unit that concentrates putative mous differentiation of the gut epithelium. Besides its role in binding sites for several transcription factors such as HNF4a and homeostasis, Cdx2 is also involved in colorectal cancers (CRC). GATA6, which synergistically stimulate the Cdx2 promoter. Indeed, its expression is altered in CRC and becomes reduced and HNF4 belongs to the superfamily of nuclear receptors, one of heterogeneous in relation to the tumor grade.4–6 This reduction the largest families of transcription factors. In mammals, two facilitates tumor progression and stimulates migration and genes encode the different HNF4a (NR2A) and HNF4g (NR2A2) dissemination of colon cancer cells,7–9 which led to attribute a isoforms. HNF4a is expressed in the liver, stomach, pancreas, 14,15 16 tumor suppressor function to Cdx2 in the gut. kidney and intestine, whereas HNF4g is mostly intestinal. Several studies have addressed the mechanisms of Cdx2 In vivo and in vitro studies have shown that HNF4a has pleiotropic 17 alteration in CRC. It does not result from allelic loss or gene roles in the liver. In the gut, HNF4a has important functions 18,19 mutation,6 suggesting rather an altered regulation. Indeed, the and is a key regulator of enterocytic markers. Conditional gene expression is downregulated in colon cancer cells by onco- knockout of the Hnf4a gene in the mouse embryonic colon genic activation of the Wnt, Ras and PI3K pathways.10–12 However, causes lethality because of the perturbation of organogenesis, 20 the transcriptional mechanisms relaying the decline of Cdx2 in cytodifferentiation and gene expression, and its ablation in CRC remain largely elusive. We have previously studied the Cdx2 the adult intestine reveals its involvement in homeostasis, cell 21 promoter during intestinal development and homeostasis using architecture and barrier function. This is consistent with a 1Inserm, Unite´ 682, Strasbourg, France; 2Faculte´ de Me´decine, Universite´ de Strasbourg, Strasbourg, France; 3Inserm, UMRS 872, Centre de Recherche des Cordeliers, Paris, France; 4UMRS 872, Universite´ Pierre et Marie Curie, Paris, France; 5UMRS 872, Universite´ Paris Descartes, Paris, France; 6Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY, USA and 7Centre Hospitalier Universitaire, Service de Gastroente´rologie, Strasbourg, France. Correspondence: Dr I Duluc, Inserm U682, 3 avenue Molie`re, 67200 Strasbourg, France. E-mail: [email protected] 8These authors contributed equally to this work. Received 5 April 2012; revised 16 July 2012; accepted 17 July 2012; published online 17 September 2012 Regulation of the tumor suppressor Cdx2 by HNF4a T Saandi et al 3783 protective role attributed to HNF4a against inflammatory bowel regulatory sequences targeted by the oncogenic pathway(s) diseases.22 involved in the malignant process in ApcD14/ þ mice. Although the role of HNF4a is well described in the normal gut, its involvement in CRC is less clear. As HNF4a binds and regulates the Cdx2 promoter in normal intestinal cells,13,23 and as the Comparison of the profiles of Cdx2, HNF4a and GATA6 in intestinal tumors expression of Cdx2 is altered in CRC with an impact on tumor progression, the aim of this study was to address whether HNF4a The 9.3-kb promoter contains an upstream regulatory segment is also a determinant for the deregulation of Cdx2 in colon required for sustained expression of Cdx2 in the adult gut cancers, as well as its relevance in these cancers. epithelium that synergistically responds to the endodermal transcription factors HNF4a and GATA6.13 To address whether these factors could have a role in the decrease of Cdx2 expression in intestinal tumors, we compared their expression patterns RESULTS in three models of intestinal cancers in mice (Figure 2a): the The 9.3-kb Cdx2 promoter contains elements for gene ApcD14/ þ and Apcmin/ þ mice that spontaneously develop adeno- deregulation during colon carcinogenesis mas in the small intestine,25,27 and mice treated with a chemical Cdx2 expression is reduced and heterogeneous in human CRC carcinogen, AOM, that develop adenocarcinomas in the distal and also strongly compromised in genetic (Apcmin/ þ or ApcD14/ þ colon about 30 weeks after repeated administration of the mice) and chemically induced (Azoxymethane (AOM) treat- carcinogen.7 Immunohistochemical staining indicated that Cdx2 ment) models of intestinal cancers in mice.6,7,24 We have expression was impaired in the small intestinal and colon tumors previously reported that a genomic segment of 9.3 kb, upstream present in the three mouse models. HNF4a was altered similar to of the Cdx2 transcription unit, contains regulatory elements Cdx2, with an obvious decrease in malignant cells compared with required for tissue-specific expression throughout adulthood in the adjacent normal epithelium. Unlike Cdx2 and HNF4a, GATA6 the normal gut.13 Here we wondered whether the sequences did not show such a decrease. Therefore, it appears that, among mediating the decline of Cdx2 in tumors are also contained within the factors synergistically involved in the control of the Cdx2 this fragment. promoter, HNF4a but not GATA6 shows an altered profile For this purpose, pCdx2-9LacZ transgenic mice in which the consistent with the perturbed expression of Cdx2 in intestinal LacZ reporter is placed under the control of the 9.3-kb promoter of tumors. Cdx213 were crossed with ApcD14/ þ mice prone to spontaneous To address whether there is also a correlation between development of intestinal tumors.25 The 9.3-kb Cdx2 promoter is HNF4a and Cdx2 in humans, we first analyzed these two proteins mostly active in the pericecal region and proximal colon,13 in a collection of 35 human colorectal adenomas previously whereas ApcD14/ þ mice develop adenomas in the proximal small described.28 Compared with the normal mucosa that exhibits intestine and precancerous aberrant crypt foci in the colon.25 a strong nuclear staining of Cdx2 and HNF4a, the nuclear staining Yet a malignant evolution of colonic lesions occurs when ApcD14/ þ became weaker or very low (Figure 2b) in adenomas, together mice are subjected to a proinflammatory stress.26 Therefore, with the appearance of cytoplasmic staining. These altered pCdx2-9LacZ;ApcD14/ þ mice were given
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