cAMP-phosphodiesterase 4D7 (PDE4D7) forms a cAMP signalosome complex with DHX9 and is implicated in prostate cancer progression

Gulliver, C., Busiau, T., Byrne, A., Findlay, J. E., Hoffmann, R. and Baillie, G. (2023) cAMP-phosphodiesterase 4D7 (PDE4D7) forms a cAMP signalosome complex with DHX9 and is implicated in prostate cancer progression. Molecular Oncology, (doi: 10.1002/1878-0261.13572) (PMID:38126155) (Early Online Publication)

Abstract

A robust body of work has demonstrated that a reduction in cAMP-specific 3′,5′-cyclic phosphodiesterase 4D isoform 7 (PDE4D7) is linked with negative prostate cancer outcomes; however, the exact molecular mechanism that underpins this relationship is unknown. Epigenetic profiling has shown that the PDE4D gene can be hyper-methylated in transmembrane serine protease 2 (TMPRSS2)–ETS transcriptional regulator ERG (ERG) gene-fusion-positive prostate cancer (PCa) tumours, and this inhibits messenger RNA (mRNA) expression, leading to a paucity of cellular PDE4D7 protein. In an attempt to understand how the resulting aberrant cAMP signalling drives PCa growth, we immunopurified PDE4D7 and identified binding proteins by mass spectrometry. We used peptide array technology and proximity ligation assay to confirm binding between PDE4D7 and ATP-dependent RNA helicase A (DHX9), and in the design of a novel cell-permeable disruptor peptide that mimics the DHX9-binding region on PDE4D7. We discovered that PDE4D7 forms a signalling complex with the DExD/H-box RNA helicase DHX9. Importantly, disruption of the PDE4D7–DHX9 complex reduced proliferation of LNCaP cells, suggesting the complex is pro-tumorigenic. Additionally, we have identified a novel protein kinase A (PKA) phosphorylation site on DHX9 that is regulated by PDE4D7 association. In summary, we report the existence of a newly identified PDE4D7–DHX9 signalling complex that may be crucial in PCa pathogenesis and could represent a potential therapeutic target.

• Item Type: Articles
• Additional Information: CG and GSB were funded by University of Glasgow MVLS Doctoral Training Programme. RH is an employee of Philips Research. JEF was funded by Prostate Cancer UK Pilot Award, TB and AB were funded by Industrial Placement PhD studentships provided jointly by the College of Veterinary, Medical and Life Sciences, Glasgow University and Philips Research.
• Status: Early Online Publication
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gulliver, Chloe and Findlay, Mrs Jane and Baillie, Professor George and Busiau, Tara and Hoffmann, Dr Ralf
• Authors: Gulliver, C., Busiau, T., Byrne, A., Findlay, J. E., Hoffmann, R., and Baillie, G.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Molecular Oncology
• Publisher: Wiley
• ISSN: 1574-7891
• ISSN (Online): 1878-0261
• Published Online: 21 December 2023
• Copyright Holders: Copyright: © 2023 The Authors
• First Published: First published in Molecular Oncology 2023
• Publisher Policy: Reproduced under a Creative Commons licence