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Nuclear receptor co-repressor functions in prostate cancer; in vitro, in vivo and in silico approaches

Battaglia, Sebastiano (2010)
Ph.D. thesis, University of Birmingham.

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Prostate epithelial cells are exquisitely sensitive to Nuclear Receptor (NR) ligands. These compounds exert anti-proliferative effect over non-malignant cells RWPE-1 while malignant PC-3 cells retain their proliferative ability. The Nuclear Receptor Co-Repressor 1 (NCOR1) complexes with Histone Deacetylases (HDACs) to repress the action of unliganded NRs, hence, inhibiting their transcriptional and phenotypical effects. NCOR1 was found to be over-expressed in PC-3 cells when compared to non-malignant RWPE-1 cells. Chemical inhibition of NCOR1, via the HDAC inhibitor SAHA, or NCOR1 knock-down, via shRNA, restored PC-3 cells sensitivity to NR agonists with exception of Vitamin D and Thyroid Hormone T3. NCOR1-knock down led also to a re-expression of basally repressed genes, as measured via Microfluidic Gene-Card analysis (Q-RTPCRm). CDKN1A was de-repressed by the knock down and its activation via VDR was modeled with a systems biology approach to identify the mechanistic events behind CDKN1A transcriptional regulation via miRNAs. Differential equation models revealed a time-sensitive activation, VDR-dependent, of the miRNA-miR106b that leads to a steep degradation of CDKN1A mRNA levels within the first 30 minutes. These results support the idea of a corrupted regulatory network that squelches NR activity in prostate epithelial cells.

Type of Work:Ph.D. thesis.
Supervisor(s):Campbell, Moray and Bunce, Christopher M.
School/Faculty:Colleges (2008 onwards) > College of Medical & Dental Sciences
Department:Institute for Biomedical Research
Subjects:RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Institution:University of Birmingham
ID Code:961
This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder.
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