Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523248
Title: Nuclear receptor co-repressor functions in prostate cancer : in vitro, in vivo and in silico approaches
Author: Battaglia, Sebastiano
Awarding Body: University of Birmingham
Current Institution: University of Birmingham
Date of Award: 2010
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Abstract:
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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.523248  DOI: Not available
Keywords: RC0254 Neoplasms. Tumors. Oncology (including Cancer)
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