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Title: The role of the polycomb group protein EZH2 in the molecular pathogenesis of prostate cancer
Author: Bryant, Richard John
ISNI:       0000 0001 2447 9069
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2008
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Although prostate cancer causes morbidity and mortality many men have indolent disease with few health consequences. There is an urgent need to identify which patients with prostate cancer require clinical intervention, thereby preventing both under- and overtreatment. The Polyeomb Group (PeG) gene EZH2 is up-regulated in hormone-refractory metastatic prostate cancer, suggesting that EZH2 promotes progression to an advanced tumour phenotype. EZH2 is a transcriptional repressor during normal embryonic development by virtue of its histone methyltransferase activity. At the start of this work the role ofEZH2 during tumour progression was unclear. This thesis identifies EZH2 as a dual-function promoter of prostate cancer progression. EZH2 function promotes proliferation of both androgen-responsive and androgen-independent prostate cancer cells, suggesting that aberrant EZH2 function may occur earlier than originally thought during prostate cancer progression. It was discovered that EZH2 function promotes prostate cancer cellular invasiveness, demonstrating a mechanism which can account for the association between increased EZH2 expression and advanced disease. It was observed that androgen-induced expression of the TMPRSS2:ERG gene fusion in prostate cancer cells was associated with a trend towards increased expression of HDAC1 and the PeG genes EZH2 and SUZ12. It was also observed that EZH2 regulates actin polymerisation in prostate cancer cells, which may account for the abrogation of cellular invasiveness observed following EZH2 knock-down. Given that EZH2 is a transcriptional repressor, a search for candidate EZH2 target genes was performed. EZH2 may promote transcriptional repression ofp21 and MMP7. . Effects of overexpression of EZH2 and a dominant gain-of-function allele, EZH2R732K, were investigated in prostate cancer cells. No discernible phenotype was observed, suggesting additional factors are required to promote the progression to an aggressive prostate cancer phenotype. The results presented in this thesis suggest mechanisms that can account for the association between increased EZH2 expression and advanced prostate cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available