GSTP1 gene repression in prostate cancer

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Glutathione S-transferases (GSTs) are a group of isoenzymes that catalyze intracellular detoxification reactions by
conjugating glutathione with electrophilic compounds including carcinogens and
exogenous drugs. Among the isoenzymes, the role of the pi class GSTP (GSTP1) in
cancer has been studied extensively. Cytosine methylation in GSTP1 regulatory
sequences associated with the loss of GSTP1 expression has been observed in a
majority of human prostate carcinomas and prostatic intraepithelial neoplasia
(PIN). In normal prostate tissue, in contrast, the CpG island of the GSTP1 gene
is not methylated and the gene is expressed. We have recently shown that
cytosine methylation can repress the GSTP1 gene expression in LNCaP prostate
cancer cells and that this effect is possibly mediated by a Methyl
Cytosine-binding Protein complex 1(MeCP1) -like complex. We will elucidate
further the mechanism of methylation-mediated GSTP1 gene repression by
determining the in vivo binding of methyl CpG binding proteins and histone
deacetylases with the GSTP1 gene promoter sequences. Since GSTP1 methylation is
an early event in prostate carcinogenesis, it has been proposed that rare
prostate cells with hypermethylated GSTP1 promoter sequences may undergo clonal
expansion because of carcinogen exposure. GSTP1 is an inhibitor of Jun
N-terminal kinase (JNK) activity and pharmacologic or genetic manipulation of
GSTP1 influences cell proliferation pathways. At present, it is not known if
loss of GSTP1 expression promotes the proliferation and/or tumorigenicity of
prostate cancer cells. We will determine if proliferation or tumorigenicity of
a human prostate cancer cell line, LNCaP, changes with expression of the GSTP1
gene.

We would expect that the results obtained from the studies will be relevant to
the development of safe and effective pharmacologic and gene-targeting
therapies for patients with human prostate cancer, and will further our
understanding of DNA methylation and cancer-associated gene silencing.
StatusFinished
Effective start/end date8/11/038/31/06

Funding

  • National Cancer Institute: $113,625.00
  • National Cancer Institute: $113,625.00

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