PIAS1 is a determinant of poor survival and acts as a positive feedback regulator of AR signaling through enhanced AR stabilization in prostate cancer

• Published in: Oncogene 2016-05, Vol.35 (18), p.2322-2332
• Main Authors: Puhr, M, Hoefer, J, Eigentler, A, Dietrich, D, van Leenders, G, Uhl, B, Hoogland, M, Handle, F, Schlick, B, Neuwirt, H, Sailer, V, Kristiansen, G, Klocker, H, Culig, Z
• Format: Article
• Language: English
• Subjects: 13; 13/105; 14; 14/63; 38; 38/109; 38/77; 631/67; 631/67/589/466; 82/80; 96; 96/2; Androgens; Androgens - pharmacology; Androstenes - pharmacology; Apoptosis; Cancer therapies; Care and treatment; Cell Biology; Cell cycle; Cell Line, Tumor; Cell Survival - drug effects; Cellular signal transduction; Development and progression; Drug Resistance, Neoplasm - drug effects; Feedback, Physiological - drug effects; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Genetic aspects; Health aspects; Hormone receptors; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Methods; Molecular targeted therapy; Oncology; Original; original-article; Phenylthiohydantoin - analogs & derivatives; Phenylthiohydantoin - pharmacology; Properties; Prostate cancer; Prostatic Neoplasms - pathology; Proteasome Endopeptidase Complex - metabolism; Protein Inhibitors of Activated STAT - deficiency; Protein Inhibitors of Activated STAT - genetics; Protein Inhibitors of Activated STAT - metabolism; Protein Stability - drug effects; Proteolysis - drug effects; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal transduction; Signal Transduction - drug effects; Survival Analysis; Transcription, Genetic - drug effects
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.292

Novel drugs like Abiraterone or Enzalutamide, which target androgen receptor (AR) signaling to improve androgen deprivation therapy (ADT), have been developed during the past years. However, the application of these drugs is limited because of occurrence of inherent or acquired therapy resistances during the treatment. Thus, identification of new molecular targets is urgently required to improve current therapeutic prostate cancer (PCa) treatment strategies. PIAS1 (protein inhibitor of activated STAT1 (signal transducer and activator of transcription-1)) is known to be an important cell cycle regulator and PIAS1-mediated SUMOylation is essential for DNA repair. In this context, elevated PIAS1 expression has already been associated with cancer initiation. Thus, in the present study, we addressed the question of whether PIAS1 targeting can be used as a basis for an improved PCa therapy in combination with anti-androgens. We show that PIAS1 significantly correlates with AR expression in PCa tissue and in cell lines and demonstrate that high PIAS1 levels predict shorter relapse-free survival. Our patient data are complemented by mechanistic and functional in vitro experiments that identify PIAS1 as an androgen-responsive gene and a crucial factor for AR signaling via prevention of AR degradation. Furthermore, PIAS1 knockdown is sufficient to decrease cell proliferation as well as cell viability. Strikingly, Abiraterone or Enzalutamide treatment in combination with PIAS1 depletion is even more effective than single-drug treatment in multiple PCa cell models, rendering PIAS1 as a promising target protein for a combined treatment approach to improve future PCa therapies.