Transcriptional regulation of prostate specific antigen and human osteocalcin genes in hormone refractory human prostate cancer cells

Hormone-refractory prostate cancer is one of the most detrimental diseases of Northern American men. It is crucial to gain new insights into the molecular mechanisms that allow the androgen-independent (AI) prostate cancer cells to invade the skeleton and proliferate in an androgen-depleted environment. To achieve this goal, we focused on studying the transcriptional regulation of human osteocalcin (hOC) and prostate specific antigen (PSA) genes. PSA is a prostate specific glycoprotein whose re-elevation during hormonal therapy usually indicates the development AI tumors. By taking advantage of the difference in basal PSA expression between two lineage-related prostate cancer cell lines (LNCaP and C4-2), we identified two AI regulatory elements (AREc and pN/H) in the PSA promoter that contribute to the activation of the PSA promoter in AI C4-2 cells in the absence of androgen stimulation. An androgen receptor dependent AI pathway appears to be involved in AREc activation in C4-2 cells, whereas a 17-bp RI site within the pN/H was shown to associate with a cell-specific transcription factor, p45, and regulates PSA promoter activity independent of AR or androgens.; The discovery of hOC expression in prostate cancer specimens has opened new windows on biology and therapy of prostate cancer bone metastasis. In this thesis, we evaluated the regulation of the osteoblast-specific hOC expression in an AI bone metastatic prostate cancer cell line, PC3. Deletion analysis of the hOC promoter has led to the establishment of the functional hierarchy of OSE1, OSE2 and AP-1/VDRE in the regulation of hOC promoter activity (OSE1 > AP-1/VDRE > OSE2) and the generation of an artificial hOC promoter which has significantly higher activity than the wild type promoter. Moreover, we have also identified three groups of transcription factors, Runx2, JunD/Fra-2 and Sp-1, which confer increased hOC promoter activity in PC3 cells by binding to the OSE2, AP-1/VDRE and OSE1 elements, respectively. The interplay among these transcription factors is involved in conferring osteomimetic properties to prostate cancer cells, and contribute greatly to the osteotrophic characteristics of prostate cancer metastasis.