The Histone Deacetylase Inhibitor SAHA Arrests Cancer Cell Growth, Up-Regulates Thioredoxin-Binding Protein-2, and Down-Regulates Thioredoxin

Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less th...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2002-09, Vol.99 (18), p.11700-11705
Main Authors: Butler, Lisa M., Zhou, Xianbo, Xu, Wei-Sheng, Scher, Howard I., Rifkind, Richard A., Marks, Paul A., Richon, Victoria M.
Format: Article
Language:English
Subjects:
Apoptosis - drug effects
Base Sequence
Biological Sciences
Carcinoma
Carrier Proteins - genetics
Cell Division - drug effects
Cell growth
Cellular biology
Cloning, Molecular
Complementary DNA
Cultured cells
DNA Primers
Down-Regulation - drug effects
Enzyme Inhibitors - pharmacology
Genes
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids - pharmacology
Messenger RNA
Molecular Sequence Data
Neoplasms - pathology
Proteins
RNA, Messenger - genetics
Thioredoxins - genetics
Transfection
Transformed cell line
Tumor Cells, Cultured
Tumors
Up-Regulation - drug effects
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Summary:Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-up-regulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.182372299