Abstract 5359: Predictive significance of EZH2 expression and H3K27me3 intensity in therapy-naïve and neoadjuvant therapy-treated metastatic prostate cancer.

Abstract

Abstract Biomarkers that predict prostate cancer (PCa) adaptation to hormone therapy are essential for developing novel therapeutic strategies to manage castration-resistant PCa (CRPC) progression. Enhancer of zeste homolog 2 (EZH2) methyltransferase, the enzymatic component of polycomb repressor complex 2 (PRC2), mediates histone 3 lysine 27 trimethylation (H3K27me3) to represses target genes. Elevated EZH2 levels and decreased PRC2 target gene expression predict poor prognosis in PCa. To test whether altered EZH2 expression and H3K27me3 mark intensity are linked to CRPC progression, we analyzed these parameters in matched primary PCa and lymph node metastasis (LN-mets) from 18 therapy naïve (TN) and neo-adjuvant hormone therapy (NHT) -treated patients. EZH2 expression was observed at varying intensities in all adenocarcinoma samples. Median EZH2 expression did not differ between TN and NHT-treated prostate tumors, but was enriched in discrete foci of varying densities in TN prostatectomy specimens while being uniformly expressed in NHT-treated specimens. In LN-mets from TN patients, EZH2 expression was uniform and reflected the predominant expression pattern observed in matched prostatectomy specimens. In the NHT-treated LN-met cohort, EZH2 expression was localized to discrete foci, however its median expression was reduced relative to the TN LN-met cohort and to both primary PCa cohorts. In contrast, H3K27me3 intensity was uniform in all specimens and on average was indistinguishable between primary PCa and LN-mets irrespective of treatment. Median EZH2 expression in patient-matched prostatectomy and LN-met specimens was directly correlated in both TN and NHT-treated cohorts. H3K27me3 intensity levels were not correlated in patient-matched prostatectomy and LN-met specimens from TN patients, but were correlated in the NHT-treated cohort. While no correlation was observed for EZH2 expression and H3K27me3 intensity within each specimen, the ratio of H3K27me3 intensity to EZH2 expression was increased in the NHT-treated LN-met cohort relative to the TN LN-met cohort and to either primary PCa cohort. This effect was driven by the decreased EZH2 expression in the LN-mets from NHT-treated patients. We conclude that EZH2 expression in LN-mets is predicted by its expression in foci of the patient-matched primary tumors from both TN and NHT-treated patients. This correlation is not observed for H3K27me3 intensity levels of TN primary tumors and LN-mets, but is strongly correlated in NHT-treated specimens. NHT treatment appears to suppress EZH2 expression in LN-mets without impacting H3K27me3 intensity levels. These results suggest that while EZH2 expression and PRC2 activity may drive phenotypic changes that promote oncogenic potential, persistence of this epigenetic signature is a better predictor of CRPC progression. Citation Format: Mitali Pandey, Ladan Fazli, Antonio Hurtado-Coll, Martin E. Gleave, Michael E. Cox. Predictive significance of EZH2 expression and H3K27me3 intensity in therapy-naïve and neoadjuvant therapy-treated metastatic prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5359. doi:10.1158/1538-7445.AM2013-5359