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Title: The role of FASN in the development and severity of prostate cancer
Author: De Piano, Mario Matthew
ISNI:       0000 0004 6497 8593
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Fatty acid synthase (FASN), a lipogenic enzyme, is responsible for the de novo synthesis of endogenously derived fatty acids in the human body including palmitate; the building block of protein palmitoylation. Recent work has suggested that alongside an established role in promoting cell proliferation FASN may also specifically promote an invasive phenotype; although this is less-well documented. Understanding the influence of FASN on cell invasion is critical given that FASN is commonly overexpressed in prostate cancer and is associated with poor survival and tumour progression. In this study it was found that the depletion of FASN altered the cellular metabolome of prostate cancer cells and decreased their rate of proliferation. Moreover, changes in prostate cancer cell morphology were found to be synonymous with FASN expression levels. In addition, FASN knockdown increased cell adhesiveness, impaired HGF-mediated cell migration and reduced 3D invasion of prostate cancer cells. These changes in migratory ability suggest that FASN can mediate actin cytoskeletal remodelling, a process known to be downstream of Rho family GTPase signalling. Here, the modulation of FASN expression was observed to impact specifically on the palmitoylation of the atypical GTPase RhoU. RhoU has previously been shown to be required to deliver paxillin serine phosphorylation to drive adhesion turnover. In this study it was found that the loss of RhoU palmitoylation led to reduced adhesion turnover downstream of paxillin serine phosphorylation. The addition of exogenous palmitate was able to rescue adhesive and morphological defects seen in FASN deleted prostate cancer cells. Interestingly, it was also observed that the expression of the Rho GTPase Cdc42 decreased concomitantly with loss of FASN expression, but this is not dependent on palmitoylation; rather the findings from this study suggest that stable Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus by modulating FASN activity and reducing the availability of in cellulo palmitate a novel relationship between RhoU and Cdc42 has been exposed which directly influences cell migration potential and provides compelling evidence that FASN activity directly supports cell migration. Additionally, a pilot patho-epidemiological study using radical prostatectomy specimens revealed an association between increased expression of FASN, RhoU and Cdc42 with prostate cancer severity.
Supervisor: Van Hemelrijck, Mieke ; Wells, Claire Marie Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available