CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer

Abstract

This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein (CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer (CRC). Specifically, we focus on the effects of CBP- and p300-mediated Wnt activity on (1) neoplastic progression; (2) the activities of butyrate, a breakdown product of dietary fiber, on cell signaling and colonic cell physiology; (3) the development of resistance to histone deacetylase inhibitors (HDACis), including butyrate and synthetic HDACis, in colonic cells; and (4) the physiology and number of cancer stem cells. Mutations of the Wnt/β-catenin signaling pathway initiate the majority of CRC cases, and we have shown that hyperactivation of this pathway by butyrate and other HDACis promotes CRC cell apoptosis. This activity by butyrate may in part explain the preventive action of fiber against CRC. However, individuals with a high-fiber diet may still develop neoplasia; therefore, resistance to the chemopreventive action of butyrate likely contributes to CRC. CBP or p300 may modify the ability of butyrate to influence colonic cell physiology since the two transcriptional coactivators affect Wnt signaling, and likely, its hyperactivation by butyrate. Also, CBP and p300 likely affect colonic tumorigenesis, as well as stem cell pluripotency. Improvement of CRC prevention and therapy requires a better understanding of the alterations in Wnt signaling and gene expression that underlie neoplastic progression, stem cell fate, and the development of resistance to butyrate and clinically relevant HDACis. Detailed knowledge of how CBP- and p300 modulate colonic cell physiology may lead to new approaches for anti-CRC prevention and therapeutics, particularly with respect to combinatorial therapy of CBP/p300 inhibitors with HDACis.

Keywords: Butyrate; CREB-binding protein; Colorectal cancer; Stem cells; Wnt; p300.

Figure 1

CREB-binding protein/p300 in neoplastic progression and Histone deacetylase inhibitors resistance, and a possible therapeutic approach. We posit that neoplastic progression (A) and resistance to HDACis (B) are associated with downregulated p300-mediated Wnt activity and relatively increased CBP-mediated Wnt signaling. Gene expression programs dependent upon CBP activity > p300 activity drive cell phenotype changes characteristic of greater neoplastic progression and HDACi resistance. Therefore, therapeutic approaches to prevent and/or reverse progression and resistance will depend upon enhancing p300-mediated Wnt activity at the expense of that mediated by CBP. Adapted from[43]. CBP: CREB-binding protein; HDACis: Histone deacetylase inhibitors.

Figure 2

Hypothetical relationship between p300 loss, butyrate-resistance, and right-sided colon cancer. Wnt/β-catenin signaling has both CBP-mediated and p300-mediated components. CBP-Wnt activity, which is repressed by the clinically relevant agent ICG-001, likely mediates colonic cell proliferation and resistance to butyrate (and other HDACis). In contrast, p300-Wnt activity likely mediates differentiation, apoptosis, and sensitivity to butyrate. Butyrate, derived from dietary fiber, enhances apoptosis of colon cancer cells, possibly acting through the p300-mediated component of Wnt/β-catenin activity. Neoplasms that arise in the proximal colon, where butyrate concentrations are highest, may be resistant to butyrate, and this resistance may arise through loss of p300 expression and activity and a greater reliance on CBP-mediated Wnt signaling. Development of these right-sided colon cancers may be prevented/threated via agents such as ICG-001 and/or other approaches that can promote p300-Wnt > CBP-Wnt activity. CBP: CREB-binding protein; HDACis: Histone deacetylase inhibitors.