Human PDE4D isoform composition is deregulated in primary prostate cancer and indicative for disease progression and development of distant metastases
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René Böttcher1,2, Kalyan Dulla3, Dianne van Strijp3, Natasja Dits1, Esther I. Verhoef5, George S. Baillie4, Geert J.L.H. van Leenders5, Miles D. Houslay6, Guido Jenster1, Ralf Hoffmann3,4
1Department of Urology, Erasmus Medical Center, Rotterdam, The Netherlands
2Department of Bioinformatics, Technical University of Applied Sciences Wildau, Wildau, Germany
3Department of Oncology Solutions and Precision Diagnostics, Philips Research Europe, Eindhoven, The Netherlands
4Institute of Cardiovascular and Medical Science, University of Glasgow, Glasgow, Scotland, UK
5Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands
6Institute of Pharmaceutical Science, King’s College London, London, UK
Ralf Hoffmann, email: [email protected]
Keywords: phosphodiesterase, cAMP, biomarker, ERG, androgen receptor
Received: February 03, 2016 Accepted: September 12, 2016 Published: September 23, 2016
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.
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