Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases

Abstract

Phosphodiesterase 4D7 was recently shown to be specifically over-expressed in localized prostate cancer, raising the question as to which regulatory mechanisms are involved and whether other isoforms of this gene family (PDE4D) are affected under the same conditions.We investigated PDE4D isoform composition in prostatic tissues using a total of seven independent expression datasets and also included data on DNA methylation, copy number and AR and ERG binding in PDE4D promoters to gain insight into their effect on PDE4D transcription.We show that expression of PDE4D isoforms is consistently altered in primary human prostate cancer compared to benign tissue, with PDE4D7 being up-regulated while PDE4D5 and PDE4D9 are down-regulated. Disease progression is marked by an overall down-regulation of long PDE4D isoforms, while short isoforms (PDE4D1/2) appear to be relatively unaffected. While these alterations seem to be independent of copy number alterations in the PDE4D locus and driven by AR and ERG binding, we also observed increased DNA methylation in the promoter region of PDE4D5, indicating a long lasting alteration of the isoform composition in prostate cancer tissues.We propose two independent metrics that may serve as diagnostic and prognostic markers for prostate disease: (PDE4D7 - PDE4D5) provides an effective means for distinguishing PCa from normal adjacent prostate, whereas PDE4D1/2 - (PDE4D5 + PDE4D7 + PDE4D9) offers strong prognostic potential to detect aggressive forms of PCa and is associated with metastasis free survival. Overall, our findings highlight the relevance of PDE4D as prostate cancer biomarker and potential drug target.

Creating a potential diagnostic for prostate cancer risk stratification (InformMDx™) by translating novel scientific discoveries concerning cAMP degrading phosphodiesterase-4D7 (PDE4D7)

“…In line with the PDE4D isoform expression pattern that we observed in the initial cell line and xenograft studies [65], across the clinical data sets we found evidence for consistent transcription of PDE4D1 and PDE4D2 short forms as well as clear evidence of consistent transcription of PDE4D5, PDE4D7 and PDE4D9 [72,73]. Inconsistent expression patterns were noted for the other long forms of PDE4D [72]. Consequently, we focused our attention on the analysis of the PDE4D1 and PDE4D2 short isoforms and the PDE4D5, PDE4D7 and PDE4D9 long forms.…”

“…In particular, we wanted to build on our original cell line and xenograft study [65] and understand which PDE4D isoforms are expressed in prostate cancer tissue and whether there are selective, disease-associated changes in PDE4D isoform expression concerning the known short (PDE4D1, PDE4D2, PDE4D6) forms and the long (PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8 and PDE4D9) forms and if this might provide a multifactorial signature for PDE4D expression in prostate cancer. In line with the PDE4D isoform expression pattern that we observed in the initial cell line and xenograft studies [65], across the clinical data sets we found evidence for consistent transcription of PDE4D1 and PDE4D2 short forms as well as clear evidence of consistent transcription of PDE4D5, PDE4D7 and PDE4D9 [72,73]. Inconsistent expression patterns were noted for the other long forms of PDE4D [72].…”

“…In developing PDE4D7 expression as a prognostic biomarker for prostate cancer, we adopted a hybrid development path, taking the initial laboratory observations through to clinical utility using a combination of primary research and re-analysis of existing public gene expression datasets [65,[70][71][72][73]. Firstly we developed an effective bio-assay for PDE4D7 that, in its early form, was sufficient for validation and assessment of clinical utility.…”

Inhibition of phosphodiesterase 4D decreases the malignant properties of DLD‑1 colorectal cancer cells by repressing the AKT/mTOR/Myc signaling pathway

“…It has been demonstrated that PDE4D is aberrantly expressed in patients with prostate cancer and tamoxifen-resistant breast cancer cells (47,48). Although a more systematic approach is required to reach any substantial conclusion, the RT-qPCR data indicated that DLD-1 cells highly express PDE4D.…”

Gene‑expression signature predicts survival benefit from postoperative chemoradiotherapy in head and neck squamous cell carcinoma

“…Phosphodiesterase 4D (PDE4D) is a subtype of metallohydrolases, and was characterized as a tumor-promoting factor in several types of cancers (14). Previous studies reported that high expression of PDE4D promotes cell proliferation and cancer growth in prostate cancer (15)(16)(17). A recent study found that PDE4D was over-expressed in nasopharyngeal carcinoma (NPC) tissues and cells.…”