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

Research

Colin D Bingle¹  ChenWei Yu²  Bernard M Corfe²  Jennifer S Waby³  Haridasan Chirakkal⁴  Gareth J Griffiths⁵  Roderick SP Benson⁵ 

[1] Department of Infection and Immunity, University of Sheffield, Medical School, S10 2RX, Beech Hill Road, Sheffield, UK;Department of Oncology, University of Sheffield, Medical School, S10 2RX, Beech Hill Road, Sheffield, UK;Department of Oncology, University of Sheffield, Medical School, S10 2RX, Beech Hill Road, Sheffield, UK;Department of Biological Sciences, University of Hull, HU6 7RX, UK;Department of Oncology, University of Sheffield, Medical School, S10 2RX, Beech Hill Road, Sheffield, UK;Kemin Industries, South Asia, Pvt.Ltd., The Trapezium, Second Floor No:39, Nelson Manickam Road, 600 029, Chennai, Tamilnadu, India;Imagen Biotech Ltd, M13 9XX, 48 Grafton Street, Manchester, UK;

关键词: Cell Cycle Arrest;    Butyrate;    HCT116 Cell;    HDAC Inhibitor;    Hydroxamic Acid;   

DOI  :  10.1186/1476-4598-9-275

 received in 2010-01-08, accepted in 2010-10-15,  发布年份 2010

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Waby et al; licensee BioMed Central Ltd. 2010. This article is published under license to 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.