Opposing Roles of Dnmt1 in Early- and Late-Stage Murine Prostate Cancer

Abstract

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.

This study was supported by NIH R21CA128062 (A.R.K.), Roswell Park Alliance Foundation (A.R.K.), 5T32CA009072 (S.R.M.K.), DOD PC060354 (S.R.M.K.), and NCI Center Grant (CA16056) (Roswell Park Cancer Institute [RPCI]).

We thank Petra Link of the Karpf lab and Ellen Karasik and Bryan Gillard of the RPCI Mouse Tumor Model Core for outstanding technical support. We thank Peter Laird (USC) for generously providing Dnmt1 hypomorphic mice and for valuable advice and David Goodrich (RPCI) for numerous helpful suggestions.