Transcriptional regulation of prostate kallikrein-like genes by androgen.

Using gene-specific synthetic oligonucleotides the expression and
regulation of kallikrein-like genes in the human prostatic cancer
cell line LNCaP were studied. Prostate-specific antigen (PSA) and
human glandular kallikrein (hGK-1) together constitute a subfamily
of serine proteases exclusively produced in the human prostate. RNA
analysis revealed that both genes are expressed in LNCaP cells with
PSA basal levels being 2-fold higher than hGK-1 levels. Both mRNAs
are induced over a period of 24 h in the presence of 3.3 nM of the
synthetic androgen mibolerone. Stimulation of PSA RNA is about 5-
fold,whereas hGK-1 stimulation is less pronounced. Nuclear run-on
analysis revealed that androgen induction of kallikrein-like genes
in LNCaP cells is a rapid event (c3 h) occurring at the level of
transcription initiation. Treatment of cells with cycloheximide
demonstrates that, while PSA/hGK-1 basal transcription strictly
depends on continuous protein synthesis, transcriptional induction
by androgen does not. This suggests the direct involvement of the
androgen receptor in the induction process independent of
additional labile protein factors necessary for kallikrein basal
transcription. A binding motif is present in the PSA and hGK-1
promoters, closely resembling the consensus sequence for
steroidresponsive elements. The androgen antagonist cyproterone
acetate was also able to stimulate transcription of kallikrein-like
genes in LNCaP cells. In contrast, androgen-dependent
transcriptional suppression of the protooncogene c-myc was strongly
counteracted by cyproterone acetate. Thus, antiandrogens act
differentially on androgen-regulated prostate-specific (PSA, hGK-1)
and growthrelated (c-myc) gene expression in LNCaP cells.