The focus of this Research Project, originally funded May 1, 1996, renewed June 1, 2002, and renewed again April 1, 2004, has been the role of CpG island hypermethylation changes targeting GSTP1, encoding the p-class glutathione S-transferase, in the pathogenesis of prostate cancer (PCA). Since its inception, Project studies have resulted in 35 peer-reviewed manuscripts (16 since the last competitive renewal) and 19 review articles published, as well as in major new insights into how PCAs likely arise. Specifically, the discovery from this Project that the most common somatic genome alteration yet described for prostate cancer, hypermethylation of the GSTP1 CpG island, appears first in proliferative inflammatory atrophy lesions, prostate cancer precursors that arise in response to inflammatory damage to the prostatic epithelium, has stimulated intense interest in the role of chronic or recurrent inflammation in prostatic carcinogenesis. For the next funding period, the major hypothesis to be addressed is that somatic CpG island hypermethylation changes, at GSTP1 and at other gene loci, arise in an inflammatory milieu as a result of increased expression and/or activity of DNMTs. Provocative preliminary data hint that reactive nitrogen species, elaborated by inflammatory cells, may drive DNA methylation by a direct effect on DNA methyltransferase function. To test this new mechanism, three Specific Aims are proposed: (1) a characterization of post-translational modifications of DNMTs, including S-nitrosation in response to nitric oxide exposure, which promote de novo DNA methylation, (2) an evaluation of genome-wide differences in DNA methylation and chromatin structure in normal and neoplastic prostate cells, and the effects of nitric oxide exposure on patterns of genome DNA methylation, and (3) an assessment of the effects of chronic inflammation on prostatic carcinogenesis in Gstp1/2+/+ versus Gstp1/2-/- mice, and on de novo GSTP1 hypermethylation in Gstp1/2-/-GSTP1+ mice.

Public Health Relevance

Prostate cancer is the most common serious cancer diagnosed in men in the United States, and a leading cause of cancer mortality. This proposal is focused on ascertaining the cause of the disease, providing the basis for its prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070196-14
Application #
8246507
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Okano, Paul
Project Start
1996-05-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
14
Fiscal Year
2012
Total Cost
$349,564
Indirect Cost
$136,415
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Munari, Enrico; Chaux, Alcides; Vaghasia, Ajay M et al. (2016) Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies. PLoS One 11:e0146302
Haffner, Michael C; Weier, Christopher; Xu, Meng Meng et al. (2016) Molecular evidence that invasive adenocarcinoma can mimic prostatic intraepithelial neoplasia (PIN) and intraductal carcinoma through retrograde glandular colonization. J Pathol 238:31-41
Wyhs, Nicolas; Walker, David; Giovinazzo, Hugh et al. (2014) Time-Resolved Fluorescence Resonance Energy Transfer Assay for Discovery of Small-Molecule Inhibitors of Methyl-CpG Binding Domain Protein 2. J Biomol Screen 19:1060-9
Aryee, Martin J; Liu, Wennuan; Engelmann, Julia C et al. (2013) DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci Transl Med 5:169ra10
Haffner, Michael C; Mosbruger, Timothy; Esopi, David M et al. (2013) Tracking the clonal origin of lethal prostate cancer. J Clin Invest 123:4918-22
Weier, Christopher; Haffner, Michael C; Mosbruger, Timothy et al. (2013) Nucleotide resolution analysis of TMPRSS2 and ERG rearrangements in prostate cancer. J Pathol 230:174-83
Haffner, Michael C; Pellakuru, Laxmi G; Ghosh, Susmita et al. (2013) Tight correlation of 5-hydroxymethylcytosine and Polycomb marks in health and disease. Cell Cycle 12:1835-41
Shinohara, Debika Biswal; Vaghasia, Ajay M; Yu, Shu-Han et al. (2013) A mouse model of chronic prostatic inflammation using a human prostate cancer-derived isolate of Propionibacterium acnes. Prostate 73:1007-15
Orr, Brent A; Haffner, Michael C; Nelson, William G et al. (2012) Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. PLoS One 7:e41036
Vaughn, Matthew P; Biswal Shinohara, Debika; Castagna, Nicole et al. (2011) Humanizing π-class glutathione S-transferase regulation in a mouse model alters liver toxicity in response to acetaminophen overdose. PLoS One 6:e25707

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