title: Polycomb-mediated silencing in neuroendocrine prostate cancer.
abstract: BACKGROUND
  Neuroendocrine 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  We 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.
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Pier-Luc
authors: PL
authors: Clermont
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, BC V5Z 1 M9 Canada.
authors: Dong
authors: D
authors: Lin
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, BC V5Z 1 M9 Canada ; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1 M9 Canada.
authors: Francesco
authors: F
authors: Crea
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Rebecca
authors: R
authors: Wu
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Hui
authors: H
authors: Xue
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Yuwei
authors: Y
authors: Wang
authors: Department of Integrative Oncology, Genetics Unit, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Kelsie L
authors: KL
authors: Thu
authors: Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Department of Integrative Oncology, Genetics Unit, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada.
authors: Wan L
authors: WL
authors: Lam
authors: Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, BC V5Z 1 M9 Canada ; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1 M9 Canada.
authors: Colin C
authors: CC
authors: Collins
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Vancouver Prostate Centre, 899 West 12th Avenue, Vancouver, BC V5Z 1 M9 Canada ; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC V5Z 1 M9 Canada.
authors: Yuzhuo
authors: Y
authors: Wang
authors: Department of Experimental Therapeutics, British Columbia Cancer Research Centre, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Interdisciplinary Oncology Program, Faculty of Medicine, University of British Columbia, 675 W 10th Avenue, Vancouver, BC V5Z 1 L3 Canada ; Department of Surgery, University of British Columbia, 910 W 10th Avenue, Vancouver, BC V5Z 4E3 Canada.
authors: Cheryl D
authors: CD
authors: Helgason
keywords: CBX2; EZH2; Epigenetics; Neuroendocrine prostate cancer; Patient-derived xenografts; Polycomb; Prognosis; Therapeutics