Affiliation:
1. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263
2. Departments of Genetics (Computational Genetics) and Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461
Abstract
ABSTRACT
Previous studies have shown that tumor progression in the
tr
ansgenic
a
denocarcinoma of
m
ouse
p
rostate (TRAMP) model is characterized by global DNA hypomethylation initiated during early-stage disease and locus-specific DNA hypermethylation occurring predominantly in late-stage disease. Here, we utilized
Dnmt1
hypomorphic alleles to examine the role of Dnmt1 in normal prostate development and in prostate cancer in TRAMP. Prostate tissue morphology and differentiation status was normal in
Dnmt1
hypomorphic mice, despite global DNA hypomethylation.
TRAMP
;
Dnmt1
hypomorphic mice also displayed global DNA hypomethylation, but were characterized by altered tumor phenotype. Specifically,
TRAMP
;
Dnmt1
hypomorphic mice exhibited slightly increased tumor incidence and significantly increased pathological progression at early ages and, conversely, displayed slightly decreased tumor incidence and significantly decreased pathological progression at advanced ages. Remarkably, hypomorphic
Dnmt1
expression abrogated local and distant site macrometastases. Thus, Dnmt1 has tumor suppressor activity in early-stage prostate cancer, and oncogenic activity in late stage prostate cancer and metastasis. Consistent with the biological phenotype, epigenomic studies revealed that
TRAMP
;
Dnmt1
hypomorphic mice show dramatically reduced CpG island and promoter DNA hypermethylation in late-stage primary tumors compared to control mice. Taken together, the data reveal a crucial role for Dnmt1 in prostate cancer and suggest that Dnmt1-targeted interventions may have utility specifically for advanced and/or metastatic prostate cancer.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
32 articles.
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