Deregulated WNT/
catenin pathway, usually resulting from mutations in the
adenomatous polyposis coli and
beta-catenin genes, drives colorectal
tumorigenesis.
Dietary fiber has been shown to have a protective role against
colorectal cancer (CRC). We have previously demonstrated that the
histone deacetylase inhibitor (HDACi)
butyrate, a fermentation product of
dietary fiber, induces WNT/
catenin hyperactivation, which promotes CRC cell apoptosis. Therefore, the ability of
butyrate to induce WNT hyperactivation and thus promote CRC cell apoptosis may in part explain the preventive function of fiber against CRC. The association between
beta-catenin and the transcriptional coactivator p300 may influence WNT/
catenin signaling and, therefore, colonic cell physiology. p300 functions as a
histone acetylase (HAT); therefore, the modulation of WNT/
catenin activity by p300 may influence the ability of the HDACi
butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that p300 affects the hyperinduction of WNT activity by
butyrate. Knockdown of p300 levels represses
butyrate-mediated WNT/
catenin activity; but still allows for
butyrate-mediated apoptosis. Overexpression of p300 stimulates basal and
butyrate-induced WNT signaling in some, but not all, CRC cell lines. We also evaluate the role of p300 in therapeutic approaches that target CBP. The small molecule
ICG-001, in clinical trial, is a specific inhibitor of CBP-mediated WNT signaling, and previous studies have suggested that p300 is required for the activity of
ICG-001. However, we report that
ICG-001 maintains full activity against CBP-mediated WNT signaling in p300-deficient cell lines, including the
butyrate-resistance line HCT-R. In addition, our findings evaluating combinatorial treatment of
ICG-001 and
butyrate in HCT-R cells may have important therapeutic implications for the treatment of
butyrate-resistant
CRCs.