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Increased EZH2 expression in prostate cancer is associated with metastatic recurrence following external beam radiotherapy

Journal article
Authors X. N. Wu
H. Scott
Sigrid Carlsson
D. D. Sjoberg
L. Cerundolo
H. Lilja
R. Prevo
G. Rieunier
V. Macaulay
G. S. Higgins
C. L. Verrill
A. D. Lamb
V. T. Cunliffe
C. Bountra
F. C. Hamdy
R. J. Bryant
Published in Prostate
Volume 79
Issue 10
Pages 1079-1089
ISSN 0270-4137
Publication year 2019
Published at Institute of Clinical Sciences, Department of Urology
Pages 1079-1089
Language en
Links dx.doi.org/10.1002/pros.23817
Keywords enhancer of zeste 2, prostate cancer, radiotherapy, histone methyltransferase activity, group protein ezh2, androgen, suppression, biochemical failure, radiation-therapy, valproic acid, DNA-damage, risk, radiosensitivity, proliferation, Endocrinology & Metabolism, Urology & Nephrology
Subject categories Urology and Nephrology

Abstract

Background Enhancer of zeste 2 (EZH2) promotes prostate cancer progression. We hypothesized that increased EZH2 expression is associated with postradiotherapy metastatic disease recurrence, and may promote radioresistance. Methods EZH2 expression was investigated using immunohistochemistry in diagnostic prostate biopsies of 113 prostate cancer patients treated with radiotherapy with curative intent. Associations between EZH2 expression in malignant and benign tissue in prostate biopsy cores and outcomes were investigated using univariate and multivariate Cox regression analyses. LNCaP and PC3 cell radiosensitivity was investigated using colony formation and gamma H2AX assays following UNC1999 chemical probe-mediated EZH2 inhibition. Results While there was no significant association between EZH2 expression and biochemical recurrence following radiotherapy, univariate analysis revealed that prostate cancer cytoplasmic and total EZH2 expression were significantly associated with metastasis development postradiotherapy (P = 0.034 and P = 0.003, respectively). On multivariate analysis, the prostate cancer total EZH2 expression score remained statistically significant (P = 0.003), while cytoplasmic EZH2 expression did not reach statistical significance (P = 0.053). No association was observed between normal adjacent prostate EZH2 expression and biochemical recurrence or metastasis. LNCaP and PC3 cell treatment with UNC1999 reduced histone H3 lysine 27 tri-methylation levels. Irradiation of LNCaP or PC3 cells with a single 2 Gy fraction with UNC1999-mediated EZH2 inhibition resulted in a statistically significant, though modest, reduction in cell colony number for both cell lines. Increased gamma H2AX foci were observed 24 hours after ionizing irradiation in LNCaP cells, but not in PC3, following UNC1999-mediated EZH2 inhibition vs controls. Conclusions Taken together, these results reveal that high pretreatment EZH2 expression in prostate cancer in diagnostic biopsies is associated with an increased risk of postradiotherapy metastatic disease recurrence, but EZH2 function may only at most play a modest role in promoting prostate cancer cell radioresistance.

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