Identification of PDE4D as a Proliferation Promoting Factor in Prostate Cancer Using a Sleeping Beauty Transposon-Based Somatic Mutagenesis Screen

Abstract

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. [Cancer Res 2009;69(10):4388-97]

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…Miething et al (2007) further explored RUNX3's cancer function in leukemia when they incorporated a drug used for treatment of Bcr-Abl-expressing leukemia, imatinib, in their retroviral mutagenesis screen-they showed that insertion of a retroviral element in the vicinity of the RUNX3 promoter results in elevated RUNX3, which in turn led to increased resistance to imatinib-induced apoptosis and thus chronic myeloid leukemia (Miething et al, 2007). Runx3 was also identified as a cancerassociated gene by Sleeping Beauty transposable elements-transposon integration at the 5 0 position of the RUNX3 gene was associated with T-cell lymphoma (Dupuy et al, 2005) and prostate cancer (Rahrmann et al, 2009 Altogether, these findings suggest that while RUNX3 inactivation is a major determinant of cancer pathogenesis (see Table 1) and clinical outcome in many cancer types, in certain tumor types, overexpression of RUNX3 is oncogenic. In other words, RUNX3 mediates context-dependent tumor suppression.…”

Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers

“…11). Interestingly, a previous study using a sleeping beauty transposon-based screen suggested that PDE4D might function as a proliferation promoting factor in prostate cancers (12). Very recently, Pullamsetti et al found that cross-talk that occurred between PDE4 and hypoxia induciblefactor signaling might promote angiogenesis in lung cancer (13).…”

Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D

“…Although the overexpression of PDE4D was generally associated with STK11 mutation in most cell lines, only lung category was appropriate for the association study with statistical confidence. PDE4D has been implicated in cancer cell proliferation and metastasis (27,28). The inhibition of PDE4 activity suppressed cell growth and induced apoptosis in human leukemia cells (29).…”