Valproic acid inhibits the proliferation of cancer cells by re-expressing cyclin D2.
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.
Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
Daria
D
Witt
Peter
P
Burfeind
Sandra
S
von Hardenberg
Lennart
L
Opitz
Gabriela
G
Salinas-Riester
Felix
F
Bremmer
Stefan
S
Schweyer
Paul
P
Thelen
Jürgen
J
Neesen
Silke
S
Kaulfuss
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D056742:Cyclin D2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology*
D000970:Antineoplastic Agents; D056742:Cyclin D2; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D014635:Valproic Acid