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 date8/11/038/31/04

Funding

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

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