Down regulation of PSA by C/EBPα is associated with loss of AR expression and inhibition of PSA promoter activity in the LNCaP cell Line

The presence of C/EBPα in normal and cancerous prostate epithelium was examined by immunochemistry. Over expression of C/EBPα in LNCaP cells was conducted with retrovirus-mediated transduction. PSA expression was examined by RT-PCR and western blot and PSA promoter activity by luciferase reporter assay.In normal prostate C/EBPα was expressed in the basal layer of the epithelium. In prostate cancer C/EBPα was detected at low levels throughout the cancers and in advanced prostate cancer C/EBPα expression was associated with decreased expression of AR and PSA. Overexpression of C/EBPα inhibited epigenetically PSA expression and was accompanied by the loss of expression of AR. Transient increase of C/EBPα inhibited the PSA promoter/enhancer activity independently of expression of AR.In LNCaP cells C/EBPα over expression inhibits expression of PSA by AR -dependent and independent mechanisms and by extinguishing AR expression provides a model for hormonal independent cell growth.The CCAAT/enhancer binding proteins (C/EBPs) are a family of transcription factors that regulate cellular differentiation in a variety of tissues [1]. The C/EBP transcription factors consist of an activation domain, a DNA-binding basic region, and a leucine-rich dimerization domain. The structure of C/EBPα and its isoforms has been well described. The predominant isoform is a 42 kDa protein with three transactivation domains in the N-terminal portion of the protein. A second isoform is a 30-kDa protein formed from a downstream initiation site that alters the transactivation domain. Both isoforms contain the same dimerization and DNA-binding domains and are influential in controlling terminal differentiation and growth of a variety of cells [2,3]. C/EBPα is expressed in numerous tissues with the highest expression in the placenta, liver, lung, skeletal muscle, pancreas, small intestine, colon and peripheral blood leukocytes. The C/EBPs in general are important regulators of cellular differentiation