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  • Original Paper
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Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation

Oncogene volume 22, pages 4807–4818 (2003)Cite this article

Abstract

Increased histone acetylation has been associated with activated gene transcription and decreased acetylation with repression. However, there is a growing number of genes known, which are downregulated by histone deacetylase (HDAC) inhibitors through unknown mechanisms. This study examines the mechanism by which the mouse mammary tumor virus (MMTV) promoter is repressed by the HDAC inhibitor, trichostatin A (TSA). We find that this repression is transcriptional in nature and that it occurs in the presence and absence of glucocorticoids. TSA decreases MMTV transcription at a rapid rate, reaching maximum in 30–60 min. In contrast with previous reports, the repression does not correlate with an inhibition of glucocorticoid-induced nuclease hypersensitivity or NF1-binding at the MMTV promoter. Surprisingly, TSA does not induce sizable increases in histone acetylation at the MMTV promoter nor does it inhibit histone deacetylation, which accompanies deactivation of the glucocorticoid-activated MMTV promoter. Repression of MMTV transcription by TSA does not depend on the chromatin organization of the promoter because a transiently transfected MMTV promoter construct with a disorganized nucleoprotein structure was also repressed by TSA treatment. Mutational analysis of the MMTV promoter indicates that repression by TSA is mediated through the TATA box region. These results suggest a novel mechanism that involves acetylation of nonhistone proteins necessary for basal transcription.

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Acknowledgements

We thank Dr Bruce Patterson (NIH) and Dr Gordon L Hager (NIH) for kindly providing plasmids pβ-actin and pM25, respectively. We are grateful to Dr S Stoney Simons for providing the plasmid pPRE-TATA-luc. We also thank Dr Anna Riegel (Georgetown University School of Medicine) and Dr Sam John (NIH) for a critical reading of the manuscript.

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Author notes

  1. Niveen M Mulholland

    Present address: Massachusetts General Hospital, Wellman 10, 50 Blossom St., Boston, MA, 02114, USA

  2. Edlyn Soeth

    Present address: Molecular Oncology, Department of General Surgery and Thoracic Surgery, Christian-Albrechts-University, 24105, Kiel, Germany

Authors and Affiliations

  1. Department of Genetics, George Washington University, Washington, 20052, DC, USA

    Niveen M Mulholland

  2. Signal Transduction Group, Laboratory of Receptor Biology and Gene Expression, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Niveen M Mulholland, Edlyn Soeth & Catharine L Smith

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  1. Niveen M Mulholland
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Correspondence to Catharine L Smith.

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Mulholland, N., Soeth, E. & Smith, C. Inhibition of MMTV transcription by HDAC inhibitors occurs independent of changes in chromatin remodeling and increased histone acetylation. Oncogene 22, 4807–4818 (2003). https://doi.org/10.1038/sj.onc.1206722

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