Keloid scars form due to an over-exuberant, fibrotic wound response in the skin of predisposed individuals. There is currently no clear genetic link identified, and limited treatment options available. Epigenetic changes in fibrosis, and specifically in keloids, are beginning to be identified and this offers potential targets for treatment. This project explored the bromodomain and extraterminal (BET) family of proteins: Brd2, Brd3 and Brd4, which function as epigenetic regulators through their binding to acetylated lysine residues, predominantly on histone proteins. We hypothesised that they would be a target of therapeutic value given that their inhibition has shown anti-proliferative and anti-inflammatory properties in other cell types. We identified an overexpression of Brd2 in keloid tissue compared to normal controls, including a possible expression of a differential Brd2 isoform. We then used a small molecule bromodomain inhibitor, I-BET151 (GSK), to investigate the effect of BET protein inhibition in primary dermal fibroblast cultures from normal skin (NDFs) and keloid scars (KDFs). We confirmed previous literature findings, in other disease models, that BET inhibition decreased proliferation, as well as the expression of the inflammatory cytokine interleukin-6 (IL-6). In addition, we identified some more novel effects of BET inhibition, including a decrease in fibroblast contraction in a collagen gel model and decreases in proteolytic activity in fibroblast cultures, as well as a more complex ex vivo tissue model. Interestingly, we also observed profound differences between NDFs and KDFs in their signalling downstream of IL-6 in serum free environments. In particular, a strong induction of pAkt was observed in KDFs after 30 minutes of cytokine stimulation, which was not seen in NDFs, and BET inhibition abrogated this. In conclusion, BET inhibition appears to offer therapeutic value in keloid scars by targeting a number of disease-associated cell behaviours, including aberrant signalling responses, which may influence the fibrotic response. Some of these effects may be of relevance in other disease contexts including cancer, where these inhibitors are currently progressing in clinical trials.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:733434 |
| Date | January 2018 |
| Creators | Bell, Rachel Emma |
| Contributors | Shaw, Tanya J. ; Dionne, Marc Stuart |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/investigating-bet-proteins-as-a-therapeutic-target-in-keloid-scarring(546987b5-6e89-4713-a30d-af7fed3d2296).html |
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