Identification of PDE4D as a proliferation promoting factor in prostate cancer using a Sleeping Beauty transposon-based somatic mutagenesis screen.
Retroviral and transposon-based mutagenesis screens in mice have been useful for identifying candidate cancer genes for some tumor types. However, many of the organs that exhibit the highest cancer rates in humans, including the prostate, have not previously been amenable to these approaches. This study shows for the first time that the Sleeping Beauty transposon system can be used to identify candidate prostate cancer genes in mice. Somatic mobilization of a mutagenic transposon resulted in focal epithelial proliferation and hyperplasia in the prostate. Efficient methods were established to identify transposon insertion sites in these lesions, and analysis of transposon insertions identified candidate prostate cancer genes at common insertion sites, including Pde4d. PDE4D was also overexpressed in human prostate cancer patient samples and cell lines, and changes in PDE4D mRNA isoform expression were observed in human prostate cancers. Furthermore, knockdown of PDE4D reduced the growth and migration of prostate cancer cells in vitro, and knockdown of PDE4D reduced the growth and proliferation rate of prostate cancer xenografts in vivo. These data indicate that PDE4D functions as a proliferation promoting factor in prostate cancer, and the Sleeping Beauty transposon system is a useful tool for identifying candidate prostate cancer genes.
Rahrmann
Eric P
EP
Department of Genetics, Cell Biology, and Development and Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Collier
Lara S
LS
Knutson
Todd P
TP
Doyal
Meghan E
ME
Kuslak
Sheri L
SL
Green
Laura E
LE
Malinowski
Rita L
RL
Roethe
Laura
L
Akagi
Keiko
K
Waknitz
Michelle
M
Huang
Wei
W
Largaespada
David A
DA
Marker
Paul C
PC
D000818:Animals; D002455:Cell Division; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016296:Mutagenesis; D016133:Polymerase Chain Reaction; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D011130:RNA Ligase (ATP) / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D014183:Transplantation, Heterologous; D019895:Transposases / Q000235:genetics*
D018076:DNA, Complementary; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; C498355:Mki67 protein, mouse; D020033:Protein Isoforms; D012334:RNA, Neoplasm; D019895:Transposases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse; D011130:RNA Ligase (ATP)