Cancer of the Prostate: Molecular Genetics
207
and 8% of primary and metastatic tu-
mor samples, respectively, whereas no
normal prostate tissues were methylated
at the CDKN2 gene promoter. Gu and
colleagues were unable to demonstrate
intragenic alterations in methylation pat-
tern in early-stage cancers, suggesting
that
P16
methylation may be involved
in disease progression rather than initia-
tion. The
π
-class glutathione-S-transferase
(
GSTP1
) gene at 11q13 is important in the
pathway, preventing damage from elec-
trophilic metabolites of carcinogens and
reactive oxygen species. Decreased GSTP1
expression was found to accompany hu-
man prostate carcinogenesis. Analysis of a
CpG island in the promoter region of the
GSTP1
gene revealed hypermethylation in
all prostate cancer specimens examined
but no aberrant methylation in 12 nonma-
lignant tissues, including BPH. Further
immunohistochemistry in 91 cases of can-
cer was unable to detect GSTP1 expression
in almost all samples (97%). These ±nd-
ings were con±rmed
in vitro
, with protein
expression limited to prostatic cell lines
with
GSTP1
alleles hypomethylated at the
promoter sequences. Additional work has
substantiated that CpG-island hyperme-
thylation is abnormal in both alleles in
most prostate cancers; in normal tissue,
the entire CpG island is unmethylated with
extensive methylation outside the
GSTP1
gene.
GSTP1
hypermethylation and asso-
ciated reduction in GSTP1 expression have
also been demonstrated in areas of PIN.
The high frequency of
GSTP1
CpG hy-
permethylation may serve as a biomarker
in prostate cancer detection and staging.
Recent study on quantitation of GSTP1 hy-
permethylation can accurately detect the
presence of cancer even in small, limited
tissue samples. It represents a promising
diagnostic marker that could be used as an
adjunct to tissue biopsy as part of prostate
cancer screening.
Another locus of hypermethylation in
the prostate has been found to be methy-
lated in cancer (
HIC1
)g
e
n
eo
nc
h
r
o
-
mosome 17p13.3. The methylation of
NotI restriction sites at D17S5 is a com-
mon occurrence in prostate cancer and
is thus postulated to be an important
step in carcinogenesis. However, nonma-
lignant prostate, but not seminal vesicle
tissues also demonstrated
HIC1
hyper-
methylation, suggesting that the locus,
and its tissue-speci±c methylation, may
be important in the organ’s suscepti-
bility to uncontrolled growth. The CpG
island in the
CD44
transcriptional regula-
tory region is also often hypermethylated.
This leads to transcriptional inactivation
of
the gene, as
with
GSTP1
,a
n
da
resultant decrease in CD44 expression.
CD44-negative cell lines, such as LNCaP,
demonstrate hypermethylation of the pro-
moter, whereas CD44-expressing cells do
not exhibit this methylation. Examina-
tion of primary prostate cancer specimens
con±rms the increased presence of CpG
hypermethylation when compared to nor-
mal tissues. Aberrant methylation has also
been found at the endothelin B (
ETB
)
receptor gene. Endothelin B is not ex-
pressed in human prostate cancer cell
lines and shows decreased binding to
endothelin-1 in prostate cancer tissues.
The low ETB expression in prostate can-
cer was correlated with methylation of
the CpG-island sequences in the
ETB
gene. Normal tissues were unmethylated
at the
ETB
transcriptional regulatory re-
gion, whereas treatment of cancer cell
lines with a demethylating agent induced
ETB
mRNA expression. Thus, CpG-island
methylation and transcriptional silencing
appear to be important in many genes
involved in prostate cancer.
previous page 881 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 883 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off