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Clinical Epigenetics

, 7:40

First Online: 03 April 2015Received: 12 November 2014Accepted: 13 March 2015

Abstract

BackgroundNeuroendocrine prostate cancer NEPC is a highly aggressive subtype of prostate cancer PCa for which the median survival remains less than a year. Current treatments are only palliative in nature, and the lack of suitable pre-clinical models has hampered previous efforts to develop novel therapeutic strategies. Addressing this need, we have recently established the first in vivo model of complete neuroendocrine transdifferentiation using patient-derived xenografts. Few genetic differences were observed between parental PCa and relapsed NEPC, suggesting that NEPC likely results from alterations that are epigenetic in nature. Thus, we sought to identify targetable epigenetic regulators whose expression was elevated in NEPC using genome-wide profiling of patient-derived xenografts and clinical samples.

ResultsOur data indicate that multiple members of the polycomb group PcG family of transcriptional repressors were selectively upregulated in NEPC. Notably, CBX2 and EZH2 were consistently the most highly overexpressed epigenetic regulators across multiple datasets from clinical and xenograft tumor tissues. Given the striking upregulation of PcG genes and other transcriptional repressors, we derived a 185-gene list termed ‘neuroendocrine-associated repression signature’ NEARS by overlapping transcripts downregulated across multiple in vivo NEPC models. In line with the striking upregulation of PcG family members, NEARS was preferentially enriched with PcG target genes, suggesting a driving role for PcG silencing in NEPC. Importantly, NEARS was significantly associated with high-grade tumors, metastatic progression, and poor outcome in multiple clinical datasets, consistent with extensive literature linking PcG genes and aggressive disease progression.

ConclusionsWe have explored the epigenetic landscape of NEPC and provided evidence of increased PcG-mediated silencing associated with aberrant transcriptional regulation of key differentiation genes. Our results position CBX2 and EZH2 as potential therapeutic targets in NEPC, providing opportunities to explore novel strategies aimed at reversing epigenetic alterations driving this lethal disease.

KeywordsNeuroendocrine prostate cancer Patient-derived xenografts Epigenetics Polycomb CBX2 EZH2 Therapeutics Prognosis Electronic supplementary materialThe online version of this article doi:10.1186-s13148-015-0074-4 contains supplementary material, which is available to authorized users.

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