CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium

Zalzali, Hassan; Naudin, Cécile; Bastide, Pauline; Quittau-Prévostel, Corinne; Yaghi, César; Poulat, Françis; Jay, Philippe; Blache, Philippe

doi:10.1038/onc.2008.331

Cited by 36 publications

(34 citation statements)

References 18 publications

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“…As SOX9 deleted of its transactivation domain represses wild-type SOX9 activity in colon cancer cells (Blache et al, 2004;Bastide et al, 2007;Zalzali et al, 2008), we reasoned that such variants may well be expressed in colon cancer cells. We thus looked for a SOX9 splice variant resulting in a protein without the transactivation domain encoded by exon3.…”

Section: Sox9 Mrna Variants Are Expressed In Colon Cancer Cellsmentioning

confidence: 99%

“…Moreover, SOX9 directly upregulates the tumor suppressor CEACAM1 (CarcinoEmbryonic Antigenrelated Cell Adhesion Molecule 1) in the intestine epithelium , while it downregulates the carcinoembryonic antigen (CEA or CEACAM5) in human colon carcinoma cells (Jay et al, 2005). SOX9 also increases apoptosis in colon tumor cells (Jay et al, 2005) and reduces cell proliferation rate, as illustrated by hyperplasia and dysplasia induced by Sox9 abrogation in the intestine epithelium (Bastide et al, 2007;Zalzali et al, 2008). The anti-proliferative activity of SOX9 was also evidenced in retinoid-treated breast cancer cell lines and melanomas (Afonja et al, 2002;Passeron et al, 2009;Muller et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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MiniSOX9, a dominant-negative variant in colon cancer cells

et al. 2011

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Inherited and acquired changes in pre-mRNA processing have significant roles in human diseases, especially cancer. Characterization of aberrantly spliced mRNAs may thus contribute to understand malignant transformation. We recently reported an anti-oncogenic potential for the SOX9 transcription factor in the colon. For instance, the Sox9 gene knock out in the mouse intestine results in an excess of proliferation with appearance of hyperplasia. SOX9 is expressed in colon cancer cells but its endogenous activity is weak. We looked for SOX9 variants that may impair SOX9 activity in colon cancer cells and we discovered MiniSOX9, a truncated version of SOX9 devoid of transactivation domain as a result of retention of the second intron. A significant overexpression of MiniSOX9 mRNA in human tumor samples compared with their matched normal tissues was observed by realtime reverse transcriptase-PCR. Immunohistochemistry revealed that MiniSOX9 is expressed at high levels in human colon cancer samples whereas it is undetectable in the surrounding healthy tissues. Finally, we discovered that MiniSOX9 behaves as a SOX9 inhibitor, inhibits protein kinase Ca promoter activity and stimulates the canonical Wnt pathway. This potential oncogenic activity of the SOX9 locus gives new insights on its role in colon cancer.

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Section: Sox9 Mrna Variants Are Expressed In Colon Cancer Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

MiniSOX9, a dominant-negative variant in colon cancer cells

et al. 2011

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“…In intestinal epithelium, some reports have suggested an antioncogenic role for SOX9 (1,12,20,34), while others have demonstrated an oncogenic role (22,23). A recent genome-scale analysis of human colorectal cancer (CRC) identified SOX9 as one of the frequently mutated genes, and mutations in SOX9 were frame-shift or nonsense mutations (8).…”

mentioning

confidence: 99%

SOX9 directly regulates IGFBP-4 in the intestinal epithelium

Shi

Chiang

Mistretta

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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SOX9 regulates cell lineage specification by directly regulating target genes in a discrete number of tissues, and previous reports have shown cell proliferative and suppressive roles for SOX9. Although SOX9 is expressed in colorectal cancer, only a few direct targets have been identified in intestinal epithelial cells. We previously demonstrated increased proliferation in Sox9-deficient crypts through loss-of-function studies, indicating that SOX9 suppresses cell proliferation. In this study, crypt epithelial cells isolated from Sox9-deficient mice were used to identify potential target genes of SOX9. Insulin-like growth factor (IGF)-binding protein 4 (IGFBP-4), an inhibitor of the IGF/IGF receptor pathway, was significantly downregulated in Sox9-deficient intestinal epithelial cells and adenoma cells of Sox9-deficient Apc Min/+ mice. Immunolocalization experiments revealed that IGFBP-4 colocalized with SOX9 in mouse and human intestinal epithelial cells and in specimens from patients with primary colorectal cancer. Reporter assays and chromatin immunoprecipitation demonstrated direct binding of SOX9 to the IGFBP-4 promoter. Overexpression of SOX9 attenuated cell proliferation, which was restored following treatment with a neutralizing antibody against IGFBP-4. These results suggest that SOX9 regulates cell proliferation, at least in part via IGFBP-4. Furthermore, the antiproliferative effect of SOX9 was confirmed in vivo using Sox9-deficient mice, which showed increased tumor burden when bred with Apc Min/+ mice. Our results demonstrate, for the first time, that SOX9 is a transcriptional regulator of IGFBP-4 and that SOX9-induced activation of IGFBP-4 may be one of the mechanisms by which SOX9 suppresses cell proliferation and progression of colon cancer.

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“…the binding of SOX9 to DNA (Bastide et al, 2007). This inhibition might result from an upregulation of groucho-related inhibitors of the β-catenin-Tcf complex (Bastide et al, 2007) and of CEACAM1, a direct SOX9 target (Jin et al, 2008;Leung et al, 2008;Zalzali et al, 2008). Indeed, the W143R SOX9 mutant, which is unable to bind DNA, is unable to inhibit the Wnt-APC pathway, although it is able to repress PKCα expression, as shown in the present study.…”

Section: Sox9-dependent Pkcα Repression Involves Sp1mentioning

confidence: 53%

“…However, the molecular mechanisms involved in these biological processes still remain to be elucidated. Up to now, CEACAM1 is the only SOX9 direct target identified in the intestinal epithelium whose gene expression is upregulated through the binding of the SOX9 HMG domain on a sequence similar to the in vitro characterized consensus sequence [A/T][A/T]CAA[A/T]G (Kamachi et al, 2000;Zalzali et al, 2008). The expression of genes encoding, for example, the CDX2 cell-differentiation marker, the carcinoembryonic antigen (CEA) or the tight-junction protein claudin 7 is inversely decreased in response to an overexpression of SOX9, but it was concluded that these repressions might be indirect, i.e.…”

Section: Introductionmentioning

confidence: 99%

A new mechanism of SOX9 action to regulate PKCα expression in the intestine epithelium

Dupasquier

Abdel-Samad

Glazer

et al. 2009

Journal of Cell Science

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Variations of protein kinase C (PKC) expression greatly influence the proliferation-to-differentiation transition (PDT) of intestinal epithelial cells and might have an important impact on intestinal tumorigenesis. We demonstrate here that the expression of PKCα in proliferating intestinal epithelial cells is repressed both in vitro and in vivo by the SOX9 transcription factor. This repression does not require DNA binding of the SOX9 high-mobility group (HMG) domain but is mediated through a new mechanism of SOX9 action requiring the central and highly conserved region of SOXE members. Because SOX9 expression is itself upregulated by Wnt-APC signaling in intestinal epithelial cells, the present study points out this transcription factor as a molecular link between the Wnt-APC pathway and PKCα. These results provide a potential explanation for the decrease of PKCα expression in colorectal cancers with constitutive activation of the Wnt-APC pathway.

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CEACAM1, a SOX9 direct transcriptional target identified in the colon epithelium

Cited by 36 publications

References 18 publications

MiniSOX9, a dominant-negative variant in colon cancer cells

MiniSOX9, a dominant-negative variant in colon cancer cells

SOX9 directly regulates IGFBP-4 in the intestinal epithelium

A new mechanism of SOX9 action to regulate PKCα expression in the intestine epithelium

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