Cdx1 inhibits human colon cancer cell proliferation by reducing beta-catenin/T-cell factor transcriptional activity.
The cessation of proliferation and the induction of differentiation are highly coordinated processes that occur continuously in the intestinal crypts. The homeodomain transcription factors Cdx1 and Cdx2 regulate intestine-specific gene expression and enterocyte differentiation. Their roles in regulating proliferation are recognized but remain poorly understood. Previously, we demonstrated that Cdx1 expression diminished the proliferation of human colon cancer cells in part by reducing cyclin D1 gene expression. In order to elucidate further the molecular mechanisms underlying this phenomenon, we first hypothesized that Cdx1 or Cdx2 expression reduces colon cancer cell proliferation by inhibiting beta-catenin/T-cell factor (TCF) transcriptional activity. We report that Cdx1 or Cdx2 expression does inhibit beta-catenin/TCF transcriptional activity in colon cancer cells. This inhibitory effect is dose-dependent and is observed in different colon cancer cell lines, and the degree of inhibition correlates with the ability of Cdx1 to reduce cell proliferation. Cdx1 expression does not alter beta-catenin protein levels or intracellular distribution nor does it induce an inhibitory TCF isoform. We also find that Cdx1 expression is lost in Min mouse polyps with increased nuclear localization of beta-catenin, suggesting that Cdx1 does not support beta-catenin-mediated transformation. Finally, we show that colon cancer cells effectively reduce Cdx2-mediated inhibition of Wnt/beta-catenin/TCF transcriptional activity when compared with other model systems. This suggests that colon cancer and possibly crypt epithelial cells can modulate the effects of Cdx2 on beta-catenin signaling and proliferation. We conclude that Cdx1 and Cdx2 inhibit colon cancer cell proliferation by blocking beta-catenin/TCF transcriptional activity.
Guo
Rong-Jun
RJ
Division of Gastroenterology, the Department of Medicine, University of Pennsylvania, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Huang
Edward
E
Ezaki
Toshihiko
T
Patel
Neesha
N
Sinclair
Kristen
K
Wu
Jinling
J
Klein
Peter
P
Suh
Eun-Ran
ER
Lynch
John P
JP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D030161:Avian Proteins; D015152:Blotting, Northern; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020895:Enterocytes / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D010641:Phenotype; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014981:Xenopus; D029867:Xenopus Proteins; D051176:beta Catenin
D030161:Avian Proteins; C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C491272:Cdx1 protein, mouse; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; D020033:Protein Isoforms; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D015534:Trans-Activators; D029867:Xenopus Proteins; D051176:beta Catenin; C000605378:cdx2 protein, Xenopus; D019938:Cyclin D1; D012260:Ribonucleases