A Model of Butyrate Activity and Resistance in CRC

Butyrate, a breakdown product of dietary fibre, may in part mediate the ability of a high-fibre diet to reduce the risk of colorectal cancer (CRC). However, CRC can still develop despite a high-fibre diet; hence, butyrate resistance may influence colonic tumorigenesis. To model butyrate resistance in vitro, butyrate-resistant cells were developed and mechanisms identified by which these cells evade the effects of butyrate. These mechanisms can be interpreted in light of the existing literature to further our understanding of butyrate resistance. The current review integrates findings from various studies from my laboratory on butyrate-resistant cells, in addition to other work in the literature, to present a model of how butyrate-resistant CRC cells balance different signalling outputs to generate the resistant phenotype. Loss of p300 expression in butyrate resistance allows increased noncanonical Wnt signalling to occur without activating differentiation pathways, AKT/PKB survival signalling is activated, and CBP-Wnt activity is maintained in the pro-proliferative range. Further, overexpression of Tcf3 suppresses butyrate-induced Wnt hyperactivation. Other factors, signalling pathways and modifying influences also affect butyrate sensitivity vs. resistance. Understanding the possible role of butyrate resistance will assist in improving chemopreventive strategies for this disease.