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The effect of histone deacetylase inhibitors on gene expression in breast cancer cell lines



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Histone deacetylase inhibitors (HDIs) are a novel class of chemotherapeutics that have potent anti-proliferative and cytotoxic properties in many cancer-derived cell lines. Research has demonstrated that these compounds can activate genes such as the cell cycle inhibitor p21WAF1, while repressing the SRC and MYC proto-oncogenes. To investigate the effects of several HDI compounds in a panel of breast cancer-derived cell lines, a reverse transcriptase qPCR (RT-qPCR) and immuno-blotting approach was used. These compounds corresponded to various classes of these therapeutic drugs, and include Trichostatin A (TSA), Apicidin, Entinostat and Mocetinostat, while the cell lines were representative of the heterogeneity of breast cancer. It was hypothesised that while these drugs demonstrate similar cellular responses such as enhanced histone acetylation, cytotoxicity and p21WAF1 induction, they have different effects on their ability to repress genes. Using qPCR techniques, the expression of the p21WAF1, SRC and MYC was analysed following HDI treatment in four cell lines. SRC repression were observed in all cell lines following TSA and Apicidin treatment, whereas the effects of Entinostat and Mocetinostat were more diverse; these compounds had no effect or induced expression of SRC in T47D, Hs578T and HCC-1419 cell lines while repressing expression in the BT-474 cell line. The expression of MYC was down-regulated with TSA only in T47D and BT474 cell lines, while Apicidin, Entinostat and Mocetinostat induced expression in all cell lines. However, these four inhibitors induced p21WAF1 while exhibiting cytotoxicity and histone acetylation. In addition, it has been illustrated in the literature that RNA polymerase II-transcribed miRNA can be epigenetically modulated by chromatin-remodelling drugs. Therefore, the expression of tumour suppressor miRNA was analysed following drug treatment, and it was observed that HDIs up-regulated the expression of certain miRNAs in a cell-specific manner. miR-129-5p was induced with TSA and Entinostat in the T47D cell line, while miR-424 increased following TSA, Entinostat and Mocetinostat treatment in T47D and Hs578T cell lines. In addition, TSA induced expression of miR-9-3p in T47D, Hs578T and HCC-1419 cell lines. It was further determined that induction of these miRNA genes down-regulated the protein and/or mRNA expression of their target genes. The data presented in this thesis highlight the complex nature and the myriad effects of these inhibitors, and suggest that certain chemotherapeutics might have a clinical advantage over others in treating certain types of breast cancer.



histone deacetylase inhibitors, breast cancer, SRC, MYC, miRNA



Master of Science (M.Sc.)






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