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Nucleic Acids Research Advance Access originally published online on June 4, 2008
Nucleic Acids Research 2008 36(12):4067-4078; doi:10.1093/nar/gkn356
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Nucleic Acids Research, 2008, Vol. 36, No. 12 4067-4078
© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

TSA downregulates Wilms tumor gene 1 (Wt1) expression at multiple levels

Mohammad Shahidul Makki1, Thorsten Heinzel2 and Christoph Englert1,3,*

1Leibniz Institute for Age Research – Fritz Lipmann Institute, Beutenbergstrasse 11, 07745, 2Institute of Biochemistry and Biophysics, Friedrich Schiller University of Jena, Philosophenweg 12, 07743 and 3Friedrich Schiller University of Jena, Fürstengraben 1, 07743 Jena, Germany

*To whom correspondence should be addressed. Tel: +49 3641 656042; Fax: +49 3641 656040; Email: cenglert{at}fli-leibniz.de

Received January 29, 2008. Revised May 19, 2008. Accepted May 20, 2008.

The Wilms tumor gene WT1 encodes a zinc-finger transcription factor that is inactivated in a subset of pediatric kidney cancers. During embryogenesis, WT1 is expressed in a time- and tissue-specific manner in various organs including gonads and kidney but also in the hematopoietic system. Although widely regarded as a tumor suppressor gene, wild-type WT1 is overexpressed in a variety of hematologic malignancies, most notably in acute lymphoblastic leukemia as well as myelodysplastic syndromes. Reduction of WT1 expression levels leads to decrease of proliferation and apoptosis of leukemic cells, suggesting that in certain contexts WT1 might act as an oncogene. We show here that histone deacetylase inhibitors like Trichostatin A (TSA) can promptly and dramatically downregulate Wt1 expression levels in different cell lines. This effect was mostly due to the cessation of transcription and was mediated by sequences located in intron 3 of Wt1. In addition, TSA also caused enhanced degradation of the Wt1 protein by the proteasome. This was at least in part due to induction of the ubiquitin-conjugating enzyme UBCH8. Thus, downregulation of Wt1 expression might contribute to the beneficial effects of histone deacetylase inhibitors that are currently used in clinical trials as cancer therapeutics.


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L. M. Green, K. J. Wagner, H. A. Campbell, K. Addison, and S. G. E. Roberts
Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation
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[Abstract] [Full Text] [PDF]


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