RESULTS: Stringent statistical analysis identifies a cohort of genes that lack one or both
androgen response elements (AREs) or
vitamin D response elements (VDREs) in their promoters, which are nevertheless differentially regulated by both
steroids (either additively or synergistically). This suggests that mechanisms in addition to VDR- and AR-mediated transcription are responsible for the modulation of gene expression. Microarray analysis shows that fifteen
miRNAs are also differentially regulated by
1,25(OH)2D3 and T. Among these miR-22, miR-29ab, miR-134, miR-1207-5p and miR-371-5p are up regulated, while miR-17 and miR-20a, members of the miR-17/92 cluster are down regulated. A number of genes implicated in cell cycle progression,
lipid synthesis and accumulation and
calcium homeostasis are among the
mRNA targets of these
miRNAs. Thus, in addition to their well characterized effects on transcription, mediated by either or both cognate
nuclear receptors,
1,25(OH)2D3 and T regulate the steady state
mRNA levels by modulating
miRNA-mediated mRNA degradation, generating attenuation feedback loops that result in global changes in
mRNA and
protein levels. Changes in genes involved in
calcium homeostasis may have specific clinical importance since the second messenger Ca2+ is known to modulate various cellular processes, including cell proliferation, cell death and cell motility, which affects
prostate cancer tumor progression and responsiveness to
therapy.
CONCLUSIONS: These data indicate that these two
hormones combine to drive a differentiated phenotype, and reinforce the idea that the age dependent decline in both
hormones results in the de-differentiation of prostate
tumor cells, which results in increased proliferation, motility and invasion common to aggressive
tumors. These studies also reinforce the potential importance of
miRNAs in
prostate cancer progression and therapeutic outcomes.