Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase

Ho Jeong Kwon, Takashi Owa, Christian A. Hassig, Junichi Shimada, Stuart L. Schreiber

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

Depudecin is a fungal metabolite that reverts the rounded phenotype of NIH 3T3 fibroblasts transformed with v-ras and v-src oncogenes to the flattened phenotype of the nontransformed parental cells. The mechanism of detransformation induced by this agent had not been determined. Here, we demonstrate that depudecin inhibits histone deacetylase (HDAC) activity effectively both in vivo and in vitro. Depudecin induces similar morphological reversion in v-ras transformed NIH 3T3 cells as do other naturally occurring HDAC inhibitors such as trichostatin A or trapoxin. It competitively inhibits the binding of [3H] trapoxin in vitro and the nuclear binding of a trapoxin-coumarin fluorophore in vivo, suggesting that depudecin shares a nuclear binding protein and site on that protein with trapoxin. Furthermore, depudecin induces hyperacetylation of histones in a dose- dependent manner and at concentrations comparable with that required for detransformation. An in vitro histone deacetylase assay, using purified recombinant HDAC1, reveals that depudecin inhibits 50% of the enzyme activity at a concentration of 4.7 μM. These results demonstrate that depudecin is a novel HDAC inhibitor and suggest that its ability to induce morphological reversion of transformed cells is the result of its HDAC inhibitory activity.

Original languageEnglish
Pages (from-to)3356-3361
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number7
DOIs
Publication statusPublished - 1998 Mar 31

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Histone Deacetylases
Fibroblasts
Histone Deacetylase Inhibitors
trichostatin A
src Genes
Phenotype
NIH 3T3 Cells
Nuclear Proteins
depudecin
Histones
Carrier Proteins
Binding Sites
trapoxin A
Enzymes
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • General

Cite this

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title = "Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase",
abstract = "Depudecin is a fungal metabolite that reverts the rounded phenotype of NIH 3T3 fibroblasts transformed with v-ras and v-src oncogenes to the flattened phenotype of the nontransformed parental cells. The mechanism of detransformation induced by this agent had not been determined. Here, we demonstrate that depudecin inhibits histone deacetylase (HDAC) activity effectively both in vivo and in vitro. Depudecin induces similar morphological reversion in v-ras transformed NIH 3T3 cells as do other naturally occurring HDAC inhibitors such as trichostatin A or trapoxin. It competitively inhibits the binding of [3H] trapoxin in vitro and the nuclear binding of a trapoxin-coumarin fluorophore in vivo, suggesting that depudecin shares a nuclear binding protein and site on that protein with trapoxin. Furthermore, depudecin induces hyperacetylation of histones in a dose- dependent manner and at concentrations comparable with that required for detransformation. An in vitro histone deacetylase assay, using purified recombinant HDAC1, reveals that depudecin inhibits 50{\%} of the enzyme activity at a concentration of 4.7 μM. These results demonstrate that depudecin is a novel HDAC inhibitor and suggest that its ability to induce morphological reversion of transformed cells is the result of its HDAC inhibitory activity.",
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Depudecin induces morphological reversion of transformed fibroblasts via the inhibition of histone deacetylase. / Kwon, Ho Jeong; Owa, Takashi; Hassig, Christian A.; Shimada, Junichi; Schreiber, Stuart L.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 95, No. 7, 31.03.1998, p. 3356-3361.

Research output: Contribution to journalArticle

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AU - Owa, Takashi

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AU - Schreiber, Stuart L.

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