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

Abstract

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.

Multi-label ℓ2-regularized logistic regression for predicting activation/inhibition relationships in human protein-protein interaction networks

“…2, inhibition relationships are predicted to exist between gene AR and the genes { CTNNB1 , PIAS1 }. In31, it has been experimentally verified that there is a significant positive correlation between PIAS1 and AR expression in the malignant tissues of prostate cancer, while the Pearson’s correlation between the expressions of these two genes is low in the benign tissues, indicating that the predicted inhibition relationship between AR and PIAS1 is consistent with the experimental evidence.…”

The Role of PIAS SUMO E3-Ligases in Cancer

“…PIAS1 and PIAS3 have been most often implicated in tumorigenesis: PIAS1 is over-expressed in prostate cancer where it suppresses p21 leading to an increased proliferation rate (26,27); PIAS1 over-expression correlates with a poor clinical outcome in multiple myeloma (28); PIAS3 is often over-expressed in colorectal cancer (CRC) (24). As described in the following sections, PIAS proteins promote tumorigenesis and cancer cell survival through the interaction with several tumor suppressors and oncogenes.…”

Linking DNA Damage and Hormone Signaling Pathways in Cancer

“…PIAS1 is elevated in primary and metastatic PCa, as well as in cells resistant to DNA damage induced by taxanes, which target microtubules. It was reported that PIAS1 interacts with AR, resulting in AR stabilization, as well as increasing AR transcriptional activity and AR-driven cancer phenotypes [65]. As such, PIAS1 is an AR co-activating molecule with therapeutic potential in combination with DNA damage (table 1).…”