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

Abstract

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 B-catenin and activation of B-catenin/TCFdependent 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 b-catenin or dnGSK3b 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)

Oncogenic and cell survival properties of the retinoic acid metabolizing enzyme, CYP26A1

“…This is in line with earlier studies suggesting that VAD is associated with carcinogenesis (Wolbach and Howe, 1925), and upregulation of CYP26A1 has recently been shown in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). If increased RA metabolism is solely responsible for the apoptogen desensitizing effect, our results would imply that in a state of RA deficiency, cells may be less susceptible to apoptosis following the acquisition of DNA damage.…”

“…Despite the fact that the CYP26 enzymes may have a similar but separate role in limiting the consequences of fluctuations in nutritional vitamin A, the possibility that pathological conditions such as cancer might involve aberrant expression of CYP26A1 has recently emerged from several studies. Accumulating evidence has shown that enhanced RA catabolic activity has been observed in various types of cancer and elevated CYP26A1 expression has been detected in a number of cancer cell types (Sonneveld et al, 1998;Van heusden et al, 1998;Shelton et al, 2006;Chang et al, 2008). On the other hand, our previous study has shown that the cells expressing CYP26A1 gain significant resistance to apoptosis because of the state of reduced bioavailability caused by the metabolic inactivation of RA (Osanai and Petkovich, 2005).…”

The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells

“…The RA-metabolizing enzyme CYP26A1 has been shown to promote cell survival and contribute to the oncogenic potential of breast carcinoma cells, suggesting that this protein has an oncogenic function (10). Consistent with this finding, enhanced RA metabolism has been observed in various types of cancer and elevated levels of CYP26A1 have been reported in a number of cancer cell types (11)(12)(13). The above-mentioned studies suggested that CYP26A1 confers unique cell-survival properties on cells and modulates the expression of a variety of genes to favor cell survival.…”

A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

“…A member of the cytochrome P450 family, CYP26A1, has recently been identified as a major RA-catabolizing enzyme, which converts RA to biologically inactive hydroxylated retinoid derivatives (Niederreither et al, 2002). CYP26A1 has been shown to be upregulated in human familial adenomatous polyposis adenomas, sporadic colon cancers and primary ovarian cancer (Downie et al, 2005;Shelton et al, 2006). Furthermore, the pattern of retinoid gene expression, including CYP26A1, has been shown to correlate with retinoid sensitivity in a panel of breast and lung cancer cell lines (Liu et al, 2005).…”