1. Long-term genistein treatment of MCF-7 cells decreases acetylated histone 3 expression and alters growth responses to mitogens and histone deacetylase inhibitors.
- Author
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Jawaid K, Crane SR, Nowers JL, Lacey M, and Whitehead SA
- Subjects
- Acetylation drug effects, Caspase 9 genetics, Caspase 9 metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cyclin D1 genetics, Cyclin D1 metabolism, Epigenesis, Genetic, Female, Gene Expression drug effects, Gene Expression Regulation, Neoplastic drug effects, Histones genetics, Humans, Anticarcinogenic Agents therapeutic use, Breast Neoplasms drug therapy, Genistein therapeutic use, Histone Deacetylase Inhibitors pharmacology, Histones metabolism, Mitogens pharmacology
- Abstract
Defects in epigenetic regulation of gene transcription play an important role in carcinogenesis of the breast and other tissues. The two most widely studied epigenetic changes are DNA methylation and acetylation of histone proteins and inhibition of these processes inhibits growth in breast cancer cell lines. These data coupled with the evidence that fetal and neonatal exposure to oestrogenic substances may lead to epigenetic changes that predispose or protect against the development of breast cancer in later life formed the basis for this study. Three histone deacetylases, valproic acid (VPA), trichostatin A (TCA) and apicidin dose-dependently inhibited basal growth in MCF-7 and MDA-MB-231 as well as the growth promoting effects of oestradiol (E(2)) and epidermal growth factor (EGF) in MCF-7 cells. The growth inhibitory responses to the DNA methyl transferase inhibitor, 5-aza-2'deoxycytidine (decitabine) were weak. HDACi's reduced the protein levels of pro-caspase 9 and cyclin D1, whereas decitabine had no effect. Long-term genistein treatment (LTGT) of MCF-7 cells markedly reduced the basal expression of acetylated histone 3 (H3) and the effects of HDACi's on increasing the levels of acetylated H3 protein. However, this was not correlated with a reduced expression of total H3 except after a high dose of VPA. LTGT inhibited growth of MCF-7 cells and the mitogenic responses to E(2) and EGF. The growth inhibitory responses to HDACI's in the presence of E(2) and EGF was significantly reduced in LTGT cells compared to control MCF-7 cells and there was evidence that LTGT maintained the protein levels of pro-caspase 9 in the presence of HDACi's. This study provides further evidence that oestrogenic substances can induce significant epigenetic changes to alter the dynamics of growth in breast cancer cell lines., (Copyright 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
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