Doig, Craig L (2011)
Ph.D. thesis, University of Birmingham.
Nuclear receptors (NRs) are essential transcription factors that participate in a diverse number of cellular functions. Many have attractive chemotherapeutic potential due to their ability to govern pathways of cellular differentiation, growth arrest and programmed cell death. There are numerous examples of NR signaling becoming disrupted in human malignancies including the prostate. Mechanisms that give rise to impaired receptor signalling are investigated herein, including pre-receptor regulation of NR ligand and epigenetically mediated hypoacetylation. Furthermore, attempts either to overcome or circumvent their disruption are investigated. In parallel to these one member of the NR subfamily was chosen for further analysis. The vitamin D receptor and its target gene CDKN1A were examined for recruitment of VDR, nuclear corepressor (NCOR1) and ppolymerase II to response elements. Using the non-malignant prostate epithelial cell line RWPE-1, and PC-3 prostate cancer cell line to represent stages of prostate disease progression the spatio-temporal binding characteristics in response to ligand were measured. These findings identified aberrant nuclear corepressor recruitment to the transcription start site of CDKN1A in malignant disease. In addition examination of coregulation of a microRNA known to target CDKN1A revealed a mechanism of NR sensitivity that is also perturbed in prostate cancer. MiR106b also showed elevated tumour and serum expression in prostate cancer, suggesting a new biomarker of VDR responsiveness.
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