Adenomatous Polyposis Coli Control of C-terminal Binding Protein-1 Stability Regulates Expression of Intestinal Retinol Dehydrogenases

Abstract

Mutations in the human adenomatous polyposis coli (APC) gene are thought to initiate colorectal tumorigenesis. The tumor suppressor function of APC is attributed primarily to its ability to regulate the WNT pathway by targeting the destruction of ␤-catenin. We report here a novel role for APC in regulating degradation of the transcriptional co-repressor C-terminalbinding protein-1 (CtBP1) through a proteasome-dependent process. Further, CtBP1 suppresses the expression of intestinal retinol dehydrogenases, which are required for retinoic acid production and intestinal differentiation. In support of a role for CtBP1 in initiation of colorectal cancer, adenomas taken from individuals with familial adenomatous polyposis contain high levels of CtBP1 protein in comparison with matched, uninvolved tissue. The relationship between APC and CtBP1 is conserved between humans and zebrafish and provides a mechanistic model explaining APC control of intestinal retinoic acid biosynthesis.Germline mutations in the adenomatous polyposis coli (APC) 2,3 tumor suppressor invariably result in familial adenomatous polyposis coli (FAP), a syndrome characterized by early onset colorectal cancer (1). The mechanism by which APC mutations cause colon tumorigenesis is attributed primarily to its role in negatively regulating canonical WNT signaling (2, 3). In this role, APC functions by targeting the transcriptional coactivator ␤-catenin for intracellular degradation through a proteasome-dependent pathway, thereby limiting its ability to associate with T cell factor/lymphoid enhancer factor nuclear transcription factors. Current evidence indicates that following APC mutation, ␤-catenin accumulates and translocates into the nucleus, where it partners with T cell factor/lymphoid enhancer factors to drive a program of cellular proliferation. As evidence for a genetic relationship between APC and WNT signaling, some studies cite the existence of rare, ␤-cateninactivating mutations in colon adenocarcinomas (4, 5). Importantly, however, these mutations do not appear to fully recapitulate the clinical phenotypes associated with APC mutation (6). This discrepancy raises the possibility of additional, ␤-cateninindependent functions for APC.A number of reports suggest that the functions of APC are not limited to its well established role in regulating canonical WNT signaling. For example, APC is reported to bind to microtubules, to regulate asymmetric cell division in Drosophila male germline stem cells, and to promote proper T-cell differentiation in mice (7-11). Further, we recently demonstrated that sporadic human colorectal carcinomas lack retinol dehydrogenases and that introduction of APC into human colon carcinoma cells lines induced the expression of the retinol dehydrogenase DHRS9 in a ␤-catenin-independent manner (12). In addition, apc mcr zebrafish lack expression of intestinal enzymes, such as rdh1l, that are required for retinoic acid production. Injection of apc mcr zebrafish embryos with mRNA encoding rdh1l or treatment with exogenous...

Retinoic Acid Inhibits β-Catenin through Suppression of Cox-2

“…Additional studies indicated that APC control of retinoic acid biosynthesis occurs through the transcriptional regulator CtBP-1 and that this control is independent of ␤-catenin (39,40). Although the regulation of retinoic acid biosynthesis appears independent of the actions of ␤-catenin, the converse may not hold true.…”

The Retinol Dehydrogenase Rdh10 Localizes to Lipid Droplets during Acyl Ester Biosynthesis

“…In contrast, mouse Dhrs9 has not been knocked out, but the zebrafish ortholog of Dhrs9 contributes to atRA production that supports gut development (8). In mammalian cells, Dhrs9 seems to function as a tumor suppressor, consistent with its poor expression in colon cancer cell lines accompanied by insubstantial atRA biosynthesis, relative to normal colon cells (9). In the frog, overexpression of Rdhe2 produces posteriorization defects, similar to those caused by atRA toxicity, whereas substantial knock-down causes embryonic lethality (10).…”

Therapeutic targeting of C-terminal binding protein in human cancer

“…Recent studies have found increased levels of CtBP1 protein in adenomas from FAP patients. 24,25 CtBP is regulated at the post-translational level by several tumors suppressors, 19,23,24 but there has been no systematic examination of CtBP1 and CtBP2 protein expression in human tumors. Since the cellular CtBP antagonist and tumor suppressor ARF is silenced due to methylation in ~22-38% of colon cancers, 34 a series of 69 resected colon cancer specimens were analyzed for tumor-specific CtBP expression levels, to probe whether CtBP overexpression occurs in human tumors and especially in those tumors lacking ARF.…”

“…The adenomatous polyposis coli tumor suppressor (APC) targets CtBP for degradation, and inactivation of this APC activity may be a necessary step in colonic adenoma formation. 24,25 Finally, the tumor suppressor ARF can also downregulate CtBP by targeting it for proteasomal degradation, inducing Bik-dependent apoptosis. 19,26 ARF is also capable of blocking CtBP-mediated repression of PTEN and by doing so, ARF can inhibit CtBP-dependent hypoxia-induced, cancer cell migration.…”