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Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line

Waby, J.S., Chirakkal, H., Yu, C.W., Griffiths, J., Benson, R.S.P., Bingle, C.D. and Corfe, B.M. (2010) Sp1 acetylation is associated with loss of DNA binding at promoters associated with cell cycle arrest and cell death in a colon cell line. Molecular Cancer, 9. Art no.275. ISSN 1476-4598

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Abstract

Butyrate, a known histone deacetylase inhibitor (HDACi) and product of fibre fermentation, is postulated to mediate the protective effect of dietary fibre against colon cancer. The transcription factor Sp1 is a target of acetylation and is known to be associated with class I HDACs, including HDAC1. Sp1 is a ubiquitous transcription factor and Sp1-regulated genes include those involved in cell cycle regulation, apoptosis and lipogenesis: all major pathways in cancer development. The only known acetylated residue of Sp1 is lysine703 which resides in the DNA binding domain. Here we show that acetylated Sp1 loses p21- and bak-promoter -binding function in vitro. Furthermore treatment with a panel of HDAC inhibitors showed clustering of activities for a subset of inhibitors, causing G2 cell cycle arrest, Sp1 acetylation, p21 and Bak over-expression, all with very similar EC50 concentrations. These HDACi activities were not distributed according to the molecular class of compound. In order to mimic loss of binding, an siRNA strategy was used to reduce Sp1 expression. This resulted in altered expression of multiple elements of the p53/p21 pathway. Taken together our data suggest a mechanistic model for the chemopreventive actions of butyrate in colon epithelial cells, and provide new insight into the differential activities some classes of HDAC inhibitors.

Item Type: Article
Copyright, Publisher and Additional Information: © 2010 Waby et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Histone Deacetylase Inhibitor; Intestinal Epithelial-Cells; Sodium-Butyrate; Growth-Inhibition; HDAC Inhibition; Down-Rregulation; Cancer Cells; Expression; Transcription; P21
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Department of Infection & Immunity
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology (Sheffield)
Depositing User: Miss Anthea Tucker
Date Deposited: 08 Dec 2010 10:37
Last Modified: 08 Feb 2013 17:29
Published Version: http://dx.doi.org/10.1186/1476-4598-9-275
Status: Published
Publisher: BioMed Central
Refereed: Yes
Identification Number: 10.1186/1476-4598-9-275
URI: http://eprints.whiterose.ac.uk/id/eprint/42710

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