Human phosphodiesterase 4D7 (PDE4D7) expression is increased in TMPRSS2-ERG-positive primary prostate cancer and independently adds to a reduced risk of post-surgical disease progression

Abstract

Background:There is an acute need to uncover biomarkers that reflect the molecular pathologies, underpinning prostate cancer progression and poor patient outcome. We have previously demonstrated that in prostate cancer cell lines PDE4D7 is downregulated in advanced cases of the disease. To investigate further the prognostic power of PDE4D7 expression during prostate cancer progression and assess how downregulation of this PDE isoform may affect disease outcome, we have examined PDE4D7 expression in physiologically relevant primary human samples.Methods:About 1405 patient samples across 8 publically available qPCR, Affymetrix Exon 1.0 ST arrays and RNA sequencing data sets were screened for PDE4D7 expression. The TMPRSS2-ERG gene rearrangement status of patient samples was determined by transformation of the exon array and RNA seq expression data to robust z-scores followed by the application of a threshold >3 to define a positive TMPRSS2-ERG gene fusion event in a tumour sample.Results:We demonstrate that PDE4D7 expression positively correlates with primary tumour development. We also show a positive association with the highly prostate cancer-specific gene rearrangement between TMPRSS2 and the ETS transcription factor family member ERG. In addition, we find that in primary TMPRSS2-ERG-positive tumours PDE4D7 expression is significantly positively correlated with low-grade disease and a reduced likelihood of progression after primary treatment. Conversely, PDE4D7 transcript levels become significantly decreased in castration resistant prostate cancer (CRPC).Conclusions:We further characterise and add physiological relevance to PDE4D7 as a novel marker that is associated with the development and progression of prostate tumours. We propose that the assessment of PDE4D7 levels may provide a novel, independent predictor of post-surgical disease progression.

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

“…Similarly, ERG seems to have a major contribution on PDE4D isoform expression, with us previously reporting that PDE4D7 is up-regulated in TMPRSS2-ERG positive PCa [16]. Here, we provided further ChIP-seq support for ERG involvement in PDE4D expression.…”

“…However, in marked contrast to this, once PCa cells become androgen insensitive/independent (castration resistant), expression of PDE4D7 declines [15, 16]. …”

Triazole‐Pyridine Dicarbonitrile Targets Phosphodiesterase 4 to Induce Cytotoxicity in Lung Carcinoma Cells

“…Studies have demonstrated that PDE4 is widely expressed in cancers of brain, lung, colorectal, prostate and promote their growth. Moreover, PDE4 inhibitors suppressed cell proliferation and induced tumor regression in the tested preclinical cancer models . Taken together, these evidences suggested that PDE4 as a potential molecular therapeutic target for cancer therapy.…”

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

“…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.…”