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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2015; 21(27): 8238-8248
Published online Jul 21, 2015. doi: 10.3748/wjg.v21.i27.8238
CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer
Michael Bordonaro, Darina L Lazarova
Michael Bordonaro, Darina L Lazarova, Department of Basic Sciences, The Commonwealth Medical College, Scranton, PA 18509, United States
Author contributions: Bordonaro M and Lazarova DL both contributed to the concept and writing of the manuscript.
Supported by National Institutes of Health (Bethesda, MD) National Cancer Institute, No. 1R15CA149589-01.
Conflict-of-interest statement: The authors have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Michael Bordonaro, PhD, Associate Professor of Molecular Biology, Department of Basic Sciences, The Commonwealth Medical College, 525 Pine Street, Scranton, PA 18509, United States. mbordonaro@tcmedc.org
Telephone: +1-570-5049646 Fax: +1-570-5049636
Received: March 30, 2015
Peer-review started: March 31, 2015
First decision: April 23, 2015
Revised: May 2, 2015
Accepted: May 27, 2015
Article in press: May 27, 2015
Published online: July 21, 2015
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: CREB-binding protein, p300, Wnt, Colorectal cancer, Butyrate, Stem cells

Core tip: Deregulated Wnt/β-catenin signaling is responsible for initiating most human colorectal cancer (CRC), and hyperactivation of this pathway by histone deacetylase inhibitors such as butyrate, derived from dietary fiber, promotes CRC cell death. The transcriptional cofactors CREB-binding protein (CBP) or p300 affect Wnt signaling and the hyperactivation of this pathway by butyrate. CBP and p300 likely affect colonic tumorigenesis, stem cell fate, and butyrate resistance in CRC. Therefore, pharmacological or genetic methodologies that target CBP- and p300-mediated Wnt activity are possible preventive or therapeutic approaches against CRC.