Abstract
Histone deacetylases (HDACs) are important in chromatin remodeling and epigenetic regulation of gene expression. Histone deacetylase inhibitors (HDACi) have highly effective anti-metastatic and anti-angiogenic activity in various types of cancer, while the molecular mechanisms involved in this process are not fully understood. In the present study, trichostatin A (TSA), a HDACi, was found to suppress MCF-7 breast carcinoma cell invasion and upregulate TET1 expression in a dose-dependent manner. TET1, a dioxygenase involved in cytosine demethylation, is downregulated during breast cancer progression. TET1 knockdown in MCF-7 cells facilitates cell invasion, inhibits the expression of tissue inhibitors of metalloproteinase 2/3 (TIMP2/3) and promotes matrix metalloproteinases (MMP) 2/9 transcriptional activity. Importantly, TET1 depletion impaired the inhibitory effect of TSA on breast cancer cell invasion. Together, these results illustrated a mechanism by which TET1 partially mediates HDACi elicited suppression of breast cancer invasion.
MeSH terms
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Adult
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Cell Movement / drug effects*
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DNA-Binding Proteins / physiology*
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Drug Screening Assays, Antitumor
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Female
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Gene Expression
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Gene Expression Regulation, Neoplastic / drug effects
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Hydroxamic Acids / pharmacology*
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MCF-7 Cells
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Matrix Metalloproteinase 2 / genetics
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Matrix Metalloproteinase 2 / metabolism
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism
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Middle Aged
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Mixed Function Oxygenases
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Neoplasm Invasiveness
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Proto-Oncogene Proteins / physiology*
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Tissue Inhibitor of Metalloproteinase-2 / genetics
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Tissue Inhibitor of Metalloproteinase-2 / metabolism
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Tissue Inhibitor of Metalloproteinase-3 / genetics
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Tissue Inhibitor of Metalloproteinase-3 / metabolism
Substances
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Antineoplastic Agents
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DNA-Binding Proteins
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Proto-Oncogene Proteins
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TIMP2 protein, human
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TIMP3 protein, human
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Tissue Inhibitor of Metalloproteinase-3
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Tissue Inhibitor of Metalloproteinase-2
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trichostatin A
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Mixed Function Oxygenases
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TET1 protein, human
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MMP2 protein, human
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Matrix Metalloproteinase 2
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MMP9 protein, human
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Matrix Metalloproteinase 9