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Title: Histone deacetylase (HDAC) inhibitors and FBXL20 in breast cancer
Author: Stavropoulou, Alexandra Vassiliki
ISNI:       0000 0001 3478 4577
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Research performed over the last decade has highlighted the role of HDAC inhibitors (HDACis) as modulators of transcriptional activity and as a potential new class of therapeutic agents against many types of malignacies including breast cancer. These drugs inhibit histone deacetylases, leading to derepression of transcription of various genes that are important for cell cycle arrest and cell death. Trichostatin A (TSA) is one of the best established HDAC inhibitors and has been shown to exhibit potent differentiating and anti-proliferative properties. My data demonstrated that treatment of the MCF-7 breast cancer cell line with TSA causes G2/M phase cell cycle arrest. I characterised the novel F-Box protein called FBXL20 and identified it as a direct target of TSA. This protein is part of a novel E3 ligase complex as it binds Skpl, CUL-I and ROC-I and forms a classical SCF complex that is responsible for ubiquitination and targeting proteins for degradation by the 26S proteasome. I further studied the differences between FBXL20 in human cells and its isoform in rat cells. My data showed that FBXL20 is localised in the cytoplasm, concentrated around the nucleus and plays a role in the TSA-induced effects in MCF-7 cells, through regulating the pro-apoptotic protein Bim. Silencing FBXL20 abolished the G2/M arrest caused by TSA treatment. Although FBXL20 is a similar protein to Skp2 they are regulated by different proteins and exert different functions. These findings provide novel data to demonstrate that known and novel HDACis induce G2/M arrest followed by cell death and that this arrest is dependent on the novel FBXL20 protein in breast cancer cells. Using these newly defined properties of HDACis, I screened a panel of potential HDACis and identified at least one to be more potent than SAHA, which is currently used in the clinical setting and showed that it is able to inhibit proliferation, cause cell cycle arrest and cell death of breast cancer cells.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available