Previous studies have shown that
tumor progression in the transgenic
adenocarcinoma of mouse prostate (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.