J Cancer 2020; 11(20):5861-5866. doi:10.7150/jca.47160
Further analysis of p300 in mediating effects of Butyrate in Colorectal Cancer Cells
Department of Medical Education, Geisinger Commonwealth School of Medicine, 525 Pine Street, Scranton, PA 18509, USA.
Bordonaro M. Further analysis of p300 in mediating effects of Butyrate in Colorectal Cancer Cells. J Cancer 2020; 11(20):5861-5866. doi:10.7150/jca.47160. Available from https://www.jcancer.org/v11p5861.htm
Butyrate, a product of dietary fiber, hyperactivates Wnt signaling in colorectal cancer (CRC) cells; this activity of butyrate is causally associated with the induction of apoptosis, and the repression of proliferation, in these cells. However, CRC can develop despite a high fiber diet; hence, butyrate resistance likely occurs during colonic neoplasia. To evaluate the mechanisms of butyrate resistance, HCT-116 CRC cells were previously made resistant to butyrate (HCT-R cell line); I observed that butyrate resistance in HCT-R cells is accompanied by repressed Wnt hyperactivation. CBP and p300 competitively bind to the Wnt signaling factor beta-catenin; CBP-Wnt activity is associated with proliferation, while p300-Wnt activity is associated with differentiation and apoptosis. While butyrate sensitive HCT-116 cells express p300, butyrate resistant HCT-R cells do not. Further, HCT-116 p300 knockout cells exhibit butyrate resistance, and restoration of p300 expression in these cells enhances butyrate sensitivity. Thus, p300 activity is a mediator of butyrate sensitivity in HCT-116-derived cell lines. In the present study, YH249, a pharmacological inhibitor of the p300-beta-catenin association, was utilized to more specifically evaluate the role of p300-Wnt signaling in butyrate responsiveness. Unexpectedly, YH249 potentiates butyrate-induced effects on apoptosis and cell proliferation in HCT-116 cells; in addition, potential off-target, p300-independent, effects of YH249 on butyrate-induced Wnt hyperactivation were observed. SW620 metastatic CRC cells express p300, but do not exhibit association of p300 with beta-catenin. Thus, I hypothesized that SW620 cells can be made butyrate resistant without loss of p300 expression, while butyrate resistance would still be associated with repressed Wnt hyperactivation; this hypothesis was confirmed. Thus, the data in toto suggest that while p300-Wnt activity is an important effector of butyrate sensitivity in some CRC cell lines, other, p300-independent pathways influencing butyrate sensitivity must also exist.
Keywords: CBP, p300, Wnt, butyrate, colorectal cancer