Upregulation of Phosphatase 1 Nuclear-Targeting Subunit (PNUTS) Is an Independent Predictor of Poor Prognosis in Prostate Cancer.

Andreas Marx,Doris Höflmayer,Hartwig Huland,David Dum,Stefan Steurer,Eike Burandt,Hans Heinzer,Guido Sauter,Jan Meiners,Franziska Büscheck,Till S Clauditz,Sarah Minner,Ronald Simon,Alexander Haese,Patrick Lebok,Thorsten Schlomm,Markus Graefen,Cosima Göbel,Andreas M Luebke,Maria Christina Tsourlakis,Christoph Fraune,Simon Kind,Jakob R Izbicki ,Claudia Hube‐Magg ,Christina Möller‐Koop

doi:10.1155/2020/7050146

Abstract

Protein phosphatase 1 nuclear-targeting subunit (PNUTS) is ubiquitously expressed and associates with PTEN and protein phosphatase 1 (PP1) to control its activity. The role of PNUTS overexpression has hardly been studied in cancer. In this study, we used immunohistochemistry to quantitate PNUTS expression on a tissue microarray containing 17,747 clinical prostate cancer specimens. As compared to normal prostate epithelium, PNUTS expression was often higher in cancer. Among 12,235 interpretable tumors, PNUTS staining was negative in 21%, weak in 34%, moderate in 35%, and strong in 10% of cases. High PNUTS expression was associated with higher tumor stage, classical and quantitative Gleason grade, nodal stage, surgical margin, Ki67 labeling index, and early biochemical recurrence (p < 0.0001 each). PNUTS expression proved to be a moderate prognostic parameter with a maximal univariable Cox proportional hazard for PSA recurrence-free survival of 2.21 compared with 5.91 for Gleason grading. It was independent from established prognostic parameters in multivariable analysis. Comparison with molecular data available from earlier studies using the same TMA identified associations between high PNUTS expression and elevated androgen receptor expression (p < 0.0001), presence of TMPRSS2:ERG fusion (p < 0.0001), and 8 of 11 chromosomal deletions (3p13, 5q21, 8p21, 10q23, 12p13, 13q14, 16q24, and 17p13; p < 0.05 each). Particularly strong associations with PTEN and 12p13 deletions (p < 0.0001 each) may indicate a functional relationship, which has already been established for PNUTS and PTEN. PNUTS had no additional role on outcome in PTEN-deleted cancers. In conclusion, the results of our study identify high PNUTS protein levels as a predictor of poor prognosis possibly linked to increased levels of genomic instability. PNUTS measurement, either alone or in combination, might be of clinical utility in prostate cancers.

Highlights

In a recent overview from Bray et al, prostate cancer is the most common cancer in males in the majority of countries in the world [1]
In 20 cases of normal prostate gland, luminal cells stained weakly positive for phosphatase nuclear-targeting subunit (PNUTS), while basal cells were negative (Figure 1(a1))
Strong staining of PNUTS was associated with advanced tumor stage (p < 0:0001), high classical and quantitative Gleason grade (p < 0:0001 each), presence of lymph node metastasis (p < 0:0001), high preoperative Prostatespecific antigen (PSA) level (p = 0:0001), and positive surgical margin (p < 0:0001)

Summary

Introduction

In a recent overview from Bray et al, prostate cancer is the most common cancer in males in the majority of countries in the world [1]. It was shown that PNUTS is an essential partner of poly (ADP-ribose) polymerase 1 in DNA repair [19], making PNUTS a potential drug target in the therapy of DNA double-strand repairdeficient tumors. One report using mRNA expression data from the Oncomine database [20] suggests that PNUTS may be upregulated in prostate cancers as compared to normal prostate tissues [10]. This observation prompted us to further investigate the role of this potentially important gene by analyzing a prostate cancer tissue microarray containing tumor samples from more than 17,000 individual patients

Materials and Methods

Results

Discussion

Conclusions

Conflicts of Interest