A nuclear shift of GSK3β protein is an independent prognostic factor in prostate cancer

// Till Eichenauer 1, 2, * , Mohammad Hussein 1, * , Claudia Hube-Magg 1 , Martina Kluth 1 , Franziska Buscheck 1 , Doris Hoflmayer 1 , Maria Christina Tsourlakis 1 , Stefan Steurer 1 , Till S. Clauditz 1 , Andreas M. Luebke 1 , Eike Burandt 1 , Waldemar Wilczak 1 , Andrea Hinsch 1 , David Dum 1 , Burkhard Beyer 3 , Thomas Steuber 3 , Hartwig Huland 3 , Markus Graefen 3 , Ronald Simon 1 , Guido Sauter 1 , Nathaniel Melling 4 , Thorsten Schlomm 5 and Sarah Minner 1 1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Department of Urology, University Medical Center, Hamburg-Eppendorf, Hamburg, Germany 3 Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 5 Department of Urology, Charite-Universitatsmedizin Berlin, Berlin, Germany * These authors contributed equally to this work Correspondence to: Ronald Simon, email: R.Simon@uke.de Keywords: GSK3beta; prostate cancer; prognosis; immunohistochemistry Received: January 16, 2019 Accepted: February 15, 2019 Published: March 01, 2019 ABSTRACT Glycogen synthase kinase 3s (GSK3s) regulates many cancer relevant cellular processes and represents a potential therapeutic target. GSK3s overexpression has been linked to adverse tumor features in many cancers, but its role in prostate cancer remains uncertain. We employed immunohistochemical GSK3s expression analysis on a tissue microarray with 12,427 prostate cancers. Cytoplasmic and nuclear GSK3s staining was separately analyzed. GSK3s staining was absent in normal prostate epithelium, whereas 57% of 9,164 interpretable cancers showed detectable GSK3s expression. Cytoplasmic staining was considered weak, moderate, and strong in 36%, 19.5% and 1.5% of tumors and was accompanied by nuclear GSK3s staining in 47% of cases. Cytoplasmic GSK3s staining as well as nuclear GSK3s accumulation was associated with advanced tumor stage, high Gleason grade, presence of lymph node metastasis and early biochemical recurrence ( p < 0.0001 each for cytoplasmic staining and nu-clear accumulation). Prognosis of GSK3s positive cancers became particularly poor if nuclear GSK3s staining was also seen ( p < 0.0001). The prognostic impact of nuclear GSK3s accumu-lation was independent of established preoperative and postoperative parameters in multivari-ate analyses ( p < 0.0001). The significant association of GSK3s expression with deletions of PTEN , 3p13 ( p < 0.0001 each), 5q21 ( p = 0.0014) and 6q15 ( p = 0.0026) suggest a role of GSK3s in the development of genomic instability. In summary, the results of our study identify GSK3s as an independent prognostic marker in prostate cancer.