Histone deacetylase inhibitors increase human arylamine N-acetyltransferase-1 expression in human tumor cells

Paterson, S, Sin, KL, Tiang, JM, Minchin, RF and Butcher, NJ (2011) Histone deacetylase inhibitors increase human arylamine N-acetyltransferase-1 expression in human tumor cells. Drug Metabolism and Disposition, 39 1: 77-82. doi:10.1124/dmd.110.036202


Author Paterson, S
Sin, KL
Tiang, JM
Minchin, RF
Butcher, NJ
Title Histone deacetylase inhibitors increase human arylamine N-acetyltransferase-1 expression in human tumor cells
Journal name Drug Metabolism and Disposition   Check publisher's open access policy
ISSN 0090-9556
1521-009X
Publication date 2011-01-01
Year available 2010
Sub-type Article (original research)
DOI 10.1124/dmd.110.036202
Open Access Status DOI
Volume 39
Issue 1
Start page 77
End page 82
Total pages 6
Place of publication Bethesda, MD, U.S.A.
Publisher American Society for Pharmacology and Experimental Therapeutics
Language eng
Abstract Arylamine N-acetyltransferase-1 (NAT1) has been associated with disorders involving folate metabolism, such as spina bifida, as well as numerous human cancers. As a result, the transcriptional and post-transcriptional regulation of NAT1 activity has been extensively studied. However, little work has been reported on the epigenetic control of NAT1 expression. Here, we demonstrate that the histone deacetylase inhibitor trichostatin A (TSA) increases NAT1 activity in human cancer cells by increasing transcription from the proximal promoter NATb. A specific Sp1 binding site was identified as essential for optimal induction of NAT1 by TSA. However, TSA did not increase the expression of Sp1 in HeLa cells. Instead, TSA increased the acetylation of histones associated with the NATb promoter. This allowed recruitment of Sp1 to the promoter along with acetylated histones. We propose that NAT1 transcription is partially repressed by the local chromatin condensation in the vicinity of NATb and that histone deacetylase inhibition leads to up-regulation of NAT1 expression via a direct change in chromatin conformation.
Formatted abstract
Arylamine N-acetyltransferase-1 (NAT1) has been associated with disorders involving folate metabolism, such as spina bifida, as well as numerous human cancers. As a result, the transcriptional and post-transcriptional regulation of NAT1 activity has been extensively studied. However, little work has been reported on the epigenetic control of NAT1 expression. Here, we demonstrate that the histone deacetylase inhibitor trichostatin A (TSA) increases NAT1 activity in human cancer cells by increasing transcription from the proximal promoter NATb. A specific Sp1 binding site was identified as essential for optimal induction of NAT1 by TSA. However, TSA did not increase the expression of Sp1 in HeLa cells. Instead, TSA increased the acetylation of histones associated with the NATb promoter. This allowed recruitment of Sp1 to the promoter along with acetylated histones. We propose that NAT1 transcription is partially repressed by the local chromatin condensation in the vicinity of NATb and that histone deacetylase inhibition leads to up-regulation of NAT1 expression via a direct change in chromatin conformation.
Copyright © 2011 by the American Society for Pharmacology and Experimental Therapeutics
Keyword Acetyltransferase Type-1
Breast cancer cells
N-acetyltransferase
SP1 site
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online September 24, 2010.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2011 Collection
School of Biomedical Sciences Publications
 
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Created: Sun, 16 Jan 2011, 10:09:59 EST