CBP Activity Mediates Effects of the Histone Deacetylase Inhibitor Butyrate on WNT Activity and Apoptosis in Colon Cancer Cells

Abstract

Mutations in the WNT/beta-catenin pathway are responsible for initiating the majority of colorectal cancers (CRCs). We have previously shown that hyperactivation of this signaling by histone deacetylase inhibitors (HDACis) such as butyrate, a fermentation product of dietary fiber, promotes CRC cell apoptosis. The extent of association between beta-catenin and the transcriptional coactivator CREB-binding protein (CBP) influences WNT/catenin signaling and, therefore, colonic cell physiology. CBP functions as a histone acetylase (HAT); therefore, we hypothesized that the modulation of WNT/catenin activity by CBP modifies the ability of the HDACi butyrate to hyperinduce WNT signaling and apoptosis in CRC cells. Our findings indicate that CBP affects the hyperinduction of WNT activity by butyrate. ICG-001, which specifically blocks association between CBP and beta-catenin, abrogates the butyrate-triggered increase in the number of CRC cells with high levels of WNT/catenin signaling. Combination treatment of CRC cells with ICG-001 and butyrate results in cell type-specific effects on apoptosis. Further, both butyrate and ICG-001 repress CRC cell proliferation, with additive effects in suppressing cell growth. Our study strongly suggests that ICG-001-like agents would be effective against butyrate/HDACi-resistant CRC cells. Therefore, ICG-001-like agents may represent an important therapeutic option for CRCs that exhibit low-fold hyperactivation of WNT activity and apoptosis in the presence of HDACis. The findings generated from this study may lead to approaches that utilize modulation of CBP activity to facilitate CRC therapeutic or chemopreventive strategies.

p300 Influences Butyrate-Mediated WNT Hyperactivation In Colorectal Cancer Cells

“…In a previous study 29, we demonstrated that ICG-001 treatment of HCT-116 and SW620 CRC cells diminished basal WNT/catenin activity and markedly repressed the hyperactivation of WNT signaling by butyrate. Further, while ICG-001 and butyrate inhibited proliferation in these cell lines, we demonstrated important cell type-specific effects of ICG-001/butyrate combinatorial treatment on CRC cell apoptosis.…”

“…ICG-001, a specific inhibitor of CBP/beta-catenin association 23-28, influences butyrate-mediated WNT/catenin activity and colonic cell physiology 29. In a previous study 29, we demonstrated that ICG-001 treatment of HCT-116 and SW620 CRC cells diminished basal WNT/catenin activity and markedly repressed the hyperactivation of WNT signaling by butyrate.…”

“…Further, while ICG-001 and butyrate inhibited proliferation in these cell lines, we demonstrated important cell type-specific effects of ICG-001/butyrate combinatorial treatment on CRC cell apoptosis. Thus, combining ICG-001 and butyrate interferes with the apoptotic response in SW620, but not HCT-116, cells, with implications for the use of ICG-001 as a chemotherapeutic agent in the human patient 29.…”

“…In a recent study 29, we utilized ICG-001 to demonstrate that CBP-mediated WNT signaling is essential for the effects of butyrate on WNT hyperactivation, and we also observed important cell type-specific effects of ICG-001/butyrate cotreatment on the induction of apoptosis.…”

WNT signaling in glioblastoma and therapeutic opportunities

“…WNT signaling inhibitors have been identified and demonstrated therapeutic efficacy in various human cancers. [140][141][142][143][144][145][146][147][148][149] However, relatively little is known about clinically applicable WNT inhibitors for the treatment of GBM. In this section, we introduce a list of WNT signaling inhibitors that can be potentially used for anti-GBM therapy.…”