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Up-regulation of CYP26A1 in Adenomatous Polyposis Coli–Deficient Vertebrates via a WNT-Dependent Mechanism: Implications for Intestinal Cell Differentiation and Colon Tumor Development

Departments of ¹ Oncological Sciences and ² Medicinal Chemistry and the ³ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah

Requests for reprints: David A. Jones, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112. Phone: 801-585-6107; Fax: 801-585-0900; E-mail: david.jones{at}hci.utah.edu.

Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene seem to underlie the initiation of many colorectal carcinomas. Loss of APC function results in accumulation of ß-catenin and activation of ß-catenin/TCF–dependent transcription. Recent studies have implicated APC in controlling retinoic acid biosynthesis during normal intestinal development through a WNT-independent mechanism. Paradoxically, however, previous studies found that dietary supplementation of Apc^MIN mice with retinoic acid failed to abrogate adenoma formation. While investigating the above finding, we found that expression of CYP26A1, a major retinoic acid catabolic enzyme, was up-regulated in Apc^MIN mouse adenomas, human FAP adenomas, human sporadic colon carcinomas, and in the intestine of apc^mcr mutant zebrafish embryos. Mechanistically, cyp26a1 induction following apc mutation is dependent on WNT signaling as antisense morpholino knockdown of tcf4 or injection of a dnLEF construct into apc^mcr mutant zebrafish suppressed expression of cyp26a1 along with known WNT target genes. In addition, injection of stabilized ß-catenin or dnGSK3ß into wild-type embryos induced cyp26a1 expression. Genetic knockdown or pharmacologic inhibition of cyp26a1 in apc^mcr mutant zebrafish embryos rescued gut differentiation defects such as expression of intestinal fatty acid–binding protein and pancreatic trypsin. These findings support a novel role for APC in balancing retinoic acid biosynthesis and catabolism through WNT-independent and WNT-dependent mechanisms. (Cancer Res 2006; 66(15): 7571-7)

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