Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells

Cited 21 time in scopus
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Title
Histone deacetylase 4 mediates SMAD family member 4 deacetylation and induces 5-fluorouracil resistance in breast cancer cells
Author(s)
S L Yu; Dong Chul Lee; J W Son; C G Park; H Y Lee; J Kang
Bibliographic Citation
Oncology Reports, vol. 30, no. 3, pp. 1293-1300
Publication Year
2013
Abstract
Histone deacetylases (HDACs) have been shown to play important roles in the regulation of chromatin remodeling by histone deacetylation, and their expression is induced in several types of cancer. In addition, they are known to be associated with resistance to anticancer drugs. However, the relevance of HDAC4 in chemoresistance remains unclear. Therefore, we investigated the interaction between HDAC4 expression and chemoresistance in breast cancer cells. We found that increased HDAC4 expression in MDA-MB-231 cells was associated with resistance to the anticancer drug 5-fluorouracil (5-FU). To verify these results, a cell line stably overexpressing HDAC4 was generated using MCF-7 cells (HDAC4OE). This cell line displayed increased 5-FU resistance, and HDAC4 knockdown in HDAC4OE cells restored 5-FU sensitivity. Consequently, we concluded that HDAC4 is a critical gene associated with 5-FU chemoresistance. Further investigation using a microarray approach revealed that 355 genes were differentially expressed following HDAC4 overexpression. Based on functional annotation of the array results, HDAC4 overexpression was found to downregulate genes related to the transforming growth factor (TGF) β signaling pathway, including SMAD4, SMAD6, bone morphogenetic protein 6, inhibitor of DNA binding 1 and TGFβ2. We also found that HDAC4 expression regulates SMAD4 expression by inducing deacetylation of histone H3 in the SMAD4 promoter region. In addition, SMAD4 knockdown in MCF-7 cells increased 5-FU resistance. In summary, our data suggest that HDAC4-mediated deacetylation of the SMAD4 promoter may lead to 5-FU resistance in breast cancer cells.
Keyword
5-fluorouracilBreast cancer cellsChemoresistanceHistone deacetylase 4SMAD family member 4
ISSN
1021-335X
Publisher
Spandidos Publ Ltd
DOI
http://dx.doi.org/10.3892/or.2013.2578
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
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