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An examination of the role androgen receptor co-factors play in male fertility and prostate cancer epigenetics

In this thesis I present an investigation of a novel steroid hormone receptor cochaperone, FKBPL, and its role in male infertility. I present evidence of proposed functional mutations in the FKBPL coding sequence within a subset of the infet1ile male population, namely, those presenting with non-obstructive azoospermia, that were not present within fertile control populations. FUl1her, I show that FKBPL exhibits a cell specific pattern of expression in human testis consistent with a role in androgen receptor signalling. I then demonstrate that increased expression of FKBPL can potentiate androgen responsive gene expression in vitro. The androgen receptor and its co-factors are important also in the development and progression of prostate cancer. I present an examination of the histone modifying enzyme and androgen receptor co-activator, LSD 1, and report that it is of limited clinical utility as a prostate cancer biomarker and is not a critical factor in the maintenance of aberrant DNA methylation at the GSTP 1 locus in prostate cancer cell lines. I present further examination of the epigenetic landscape of prostate cancer using a panel of prostate cell lines representing progression from normal to late stage androgen-insensitive prostate cancer. I have demonstrated that a loss of epigenetic control at a specific set of gene loci correlates with malignant transformation while epigenetic control at other gene classes is maintained. Transcriptional analysis of candidate genes, coupled with analysis of associated promoter CpG density, reveals some genes that are repot1ed to be hypermethylated and silenced in prostate cancer to possess low density CpG promoters whose methylation is likely to be inconsequential to transcriptional regulation. This suggests that a reevaluation of purported candidate biomarkers in light of recent developments in our understanding of CpG promoter regulation might be necessary. FUl1her, I find that coordinate changes in the expression of in silica identified targets of methylation that are also androgen responsive is not characteristic of disease progression in prostate cancer, though some genes identified in this screen were able to discriminate normal from disease cells based on their transcriptional profile. I also show that epigenetic aberrations may be pharmacologically reversed, but that normal control of a subset of genes is lost as a consequence. This work collectively highlights the potential diagnostic and therapeutic translational applications of our growing understanding of the human epigenome in prostate cancer, and highlights some important considerations in the interpretation of epigenetic data in the prostate cancer field.
Date January 2013
CreatorsLagan, Kevin J.
PublisherUlster University
Source SetsEthos UK
Detected LanguageEnglish
TypeElectronic Thesis or Dissertation

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