Abstract
Histone acetylase and histone deacetylase are two crucial enzymes that determine the structure of chromatin, regulating gene expression. In this study, we observed that trichostatin A (TSA), a specific histone deacetylase inhibitor, could effectively inhibit the growth of v-Src-transformed (IV5) cells and abrogate their ability to form colonies in soft agar. Further analysis demonstrated that, although TSA reduced the expression of Eps8 in a dose- and time-dependent manner, both the protein expression and kinase activity of v-Src remained constant, and the abundance and phosphotyrosine levels of Src substrates, including cortactin, focal adhesion kinase, p130(Cas), paxillin, and Shc, were not altered. Notably, removal of TSA from the medium restored not only the expression of Eps8, but also cellular growth. Northern and reverse transcription-PCR analyses revealed the significant reduction of eps8 transcripts in TSA-treated IV5 cells relative to control cells. When active Src-expressing chicken embryonic cells were forced to overexpress p97(Eps8), they became resistant to TSA-mediated anti-proliferation. Furthermore, using small interference RNA of eps8, we demonstrated the requirement for Eps8 in IV5 cell proliferation. Thus, our results highlight a critical role for p97(Eps8) in TSA-exerted growth inhibition of v-Src-transformed cells.
Highlights
Eucaryotic DNA is regularly packed into nucleosomes that are folded into higher chromatin fibers [1]
Using small interference RNA of eps8, we demonstrated the requirement for Eps8 in IV5 cell proliferation
Ϳ2 ng/ml trichostatin A (TSA) could repress 50% colony formation of IV5 cells in soft agar (Fig. 1B). These results indicate that TSA is an effective growth and transformation inhibitor for cells expressing v-Src
Summary
Eucaryotic DNA is regularly packed into nucleosomes that are folded into higher chromatin fibers [1]. When active Src-expressing chicken embryonic cells were forced to overexpress p97Eps8, they became resistant to TSA-mediated anti-proliferation. We demonstrate a strong correlation between TSA-mediated anti-carcinogenesis and the reduced expression of Eps8, which could be attributable to diminished eps8 transcript levels in v-Src-transformed cells.
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