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

[摘要] 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.

[发布机构] University:University of Birmingham;Department:Institute of Biomedical Research

[关键词] R Medicine;RC Internal medicine;RC0254 Neoplasms. Tumors. Oncology (including Cancer)