In this study, primary murine
prostate cancer (PCa) cells were derived using the well-established TRAMP model. These PCa cells were treated with the
histone deacetylase inhibitor,
valproic acid (VPA), and we demonstrated that VPA treatment has an antimigrative, antiinvasive and antiproliferative effect on PCa cells. Using microarray analyses, we discovered several candidate genes that could contribute to the cellular effects we observed. In this study, we could demonstrate that VPA treatment of PCa cells causes the re-expression of
cyclin D2, a known regulator that is frequently lost in PCa as we could show using immunohistochemical analyses on PCa specimens. We demonstrate that VPA specifically induces the re-expression of
cyclin D2, one of the highly conserved D-type
cyclin family members, in several
cancer cell lines with weak or no
cyclin D2 expression. Interestingly, VPA treatment had no effect in fibroblasts, which typically have high basal levels of
cyclin D2 expression. The re-expression of
cyclin D2 observed in PCa cells is activated by increased
histone acetylation in the promoter region of the Ccnd2 gene and represents one underlying molecular mechanism of VPA treatment that inhibits the proliferation of
cancer cells. Altogether, our results confirm that VPA is an anticancer therapeutic
drug for the treatment of
tumors with epigenetically repressed
cyclin D2 expression.