Polycomb-mediated silencing in neuroendocrine prostate cancer

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0074-4) contains supplementary material, which is available to authorized users.

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

“…This study also identified 185 PcG target genes that were significantly down-regulated indicating a relevant role of PcG complexes in NEPC. This 'neuroendocrine-associated repression signature' (NEARS) is associated with higher-grade neoplasms, metastatic progression, and poor outcome in multiple clinical datasets [26]. In line with this model, we also found that the chromatin modifier DEK is up-regulated in NEPC cells, and that targeting this gene reduces NEPC proliferation and migration [53].…”

“…To identify the mechanisms of NEPC initiation, we conducted transcriptomic and genomic analyses on our ADT-induced NEPC model (LTL-331R) and on its hormone-sensitive predecessor (LTL-331). We found that the two models share identical genetic profiles, suggesting that genetic alterations may not exclusively drive NEPC trans-differentiation [36].Interestingly, our analysis revealed that CBX2 and EZH2 (PcG members) were significantly up-regulated in NEPC pre-clinical models and clinical samples [26]. This study also identified 185 PcG target genes that were significantly down-regulated indicating a relevant role of PcG complexes in NEPC.…”

“…Interestingly, our analysis revealed that CBX2 and EZH2 (PcG members) were significantly up-regulated in NEPC pre-clinical models and clinical samples [26]. This study also identified 185 PcG target genes that were significantly down-regulated indicating a relevant role of PcG complexes in NEPC.…”

“…More recently, we reported that a patient-derived prostate adenocarcinoma xenograft model (LTL331) developed complete NEPC relapse (LTL331R) upon castration. Notably, the original hormone-sensitive adenocarcinoma and the derived NEPC exhibited matching genetic profiles [26]. Furthermore, an analysis of ERG rearrangement and TP53 status in clinical samples with mixed NEPC/adenocarcinoma phenotype suggested a single clonal origin for the two PCa subtypes, thereby supporting the trans-differentiation model [13,[27][28][29][30][31].…”

“…Although the diagnosis of de novo NEPC is rare, sparse NEPC clones often coexist with more abundant adenocarcinoma cells. Upon repeated cycles of hormonal therapy, NEPC clones can become the dominant population [10,26,32]. AR-negative NEPC cells easily adapt to androgen deprivation and are highly proliferative (more than 50% of tumor cells in NEPCs are positive for Ki67 IHC staining) [1,21,26].…”