BACKGROUND: The transition from androgen-dependent to androgen-independent
prostate cancer is not fully understood but appears to involve multiple
genetic changes. We have identified a gene, GC79, that is more highly
expressed in androgen-dependent LNCaP-FGC human prostate cancer cells than
in androgen-independent LNCaP-LNO human prostate cancer cells. Physiologic
levels (0.1 nM:) of androgens repress expression of GC79 messenger RNA
(mRNA) in LNCaP-FGC cells. To determine the role of GC79, we cloned its
complementary DNA (cDNA) and functionally characterized its product.
METHODS: The differentially expressed GC79 gene was cloned from human
prostate cDNA libraries, sequenced, and transfected into mammalian cells
to study its function. Expression of GC79 was analyzed in various adult
and fetal human tissues and in prostate glands of castrated rats. The
association of GC79 expression and apoptosis was investigated in COS-1 and
LNCaP cells transfected with GC79 cDNA. All statistical tests are
two-sided. RESULTS: Sequence analysis indicates that GC79 encodes a large,
complex, multitype zinc-finger protein, containing nine C(2)H(2)-type
zinc-finger domains, a cysteine-rich region, and a GATA C(4)-type
zinc-finger domain. Castration-induced androgen withdrawal increased the
expression of GC79 mRNA in the regressing rat ventral prostate, suggesting
that the expression of GC79 mRNA is associated with the process of
apoptotic cell death in the rat ventral prostate. Transfection and
induction of GC79 cDNA in both COS-1 and LNCaP prostate cancer cells led
to an apoptotic index that was eightfold higher (P:<.001, two-sided
Student's t test) than that observed in uninduced transfected cells.
CONCLUSIONS: We have cloned an androgen-repressible gene, GC79, that is
potentially involved in apoptosis. This finding may have implications for
the development of androgen-independent prostate cancer and, ultimately,
for the treatment of prostate cancer
