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

René Böttcher,Esther I Verhoef,Guido Jenster,Kalyan Dulla,George S Baillie,Geert J.L.H Van Leenders,Dianne Van Strijp,Natasja Dits,Ralf Hoffmann,Miles D Houslay

doi:10.18632/oncotarget.12204

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.

Highlights

With an estimated 417,000 new cases in 2014 in Europe, prostate cancer (PCa) remains the most often diagnosed gender-specific carcinoma for men [1]
Our analysis revealed that many PDE4D isoforms are seemingly expressed at stable levels when using Exon Arrays, whereas only PDE4D1/2, PDE4D5, PDE4D7, and PDE4D9 were detectable at higher levels in our independent qRT-PCR cohort of prostate tissues
These findings were supported by the TCGA PRAD RNA-seq cohort, which mostly agreed with RT-PCR results, despite few outlier samples showing expression of other isoforms (Supplementary Figure S6)

Summary

Introduction

With an estimated 417,000 new cases in 2014 in Europe, prostate cancer (PCa) remains the most often diagnosed gender-specific carcinoma for men [1]. The metabolism of cAMP in cells is complex and tailored by spatial and signalling cross-talk considerations involving both a large family of adenylyl cyclases responsible for its synthesis, and a large family of cyclic nucleotide phosphodiesterases (PDEs) responsible for its degradation [5]. Changes in the expression of distinct PDE isoforms can be expected to reprogram downstream signalling pathways during disease development and progression, providing potential targets for novel markers and therapeutic interventions [6]. CAMP-degrading PDEs have been associated with several diseases in recent years, including stroke, acrodysostosis and COPD [9,10,11,12,13,14], and more recently, expression of a specific PDE4D isoform (PDE4D7) has been related to prostate cancer [15, 16]

Methods

Results

Conclusion