KLF4 regulation in intestinal epithelial cell maturation.
The Krüppel-like factor 4 (KLF4) transcription factor suppresses tumorigenesis in gastrointestinal epithelium. Thus, its expression is decreased in gastric and colon cancers. Moreover, KLF4 regulates both differentiation and growth that is likely fundamental to its tumor suppressor activity. We dissected the expression of Klf4 in the normal mouse intestinal epithelium along the crypt-villus and cephalo-caudal axes. Klf4 reached its highest level in differentiated cells of the villus, with levels in the duodenum>jejunum>ileum, in inverse relation to the representation of goblet cells in these regions, the lineage previously linked to KLF4. In parallel, in vitro studies using HT29cl.16E and Caco2 colon cancer cell lines clarified that KLF4 increased coincident with differentiation along both the goblet and absorptive cell lineages, respectively, and that KLF4 levels also increased during differentiation induced by the short chain fatty acid butyrate, independently of cell fate. Moreover, we determined that lower levels of KLF4 expression in the proliferative compartment of the intestinal epithelium are regulated by the transcription factors TCF4 and SOX9, an effector and a target, respectively, of beta-catenin/Tcf signaling, and independently of CDX2. Thus, reduced levels of KLF4 tumor suppressor activity in colon tumors may be driven by elevated beta-catenin/Tcf signaling.
Flandez
M
M
Department of Oncology, Albert Einstein Cancer Center, Montefiore Medical Center, 111 East 210th St. Bronx, NY 10467, USA. mflandez@montefiore.org
Guilmeau
S
S
Blache
P
P
Augenlicht
L H
LH
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002087:Butyrates / Q000494:pharmacology; D000071616:CDX2 Transcription Factor; D018938:Caco-2 Cells; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000502:physiology; D005786:Gene Expression Regulation; D019073:HT29 Cells; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000502:physiology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D055758:SOX9 Transcription Factor / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000502:physiology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002087:Butyrates; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors