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.

Centromere protein‐A (CENP‐A), a histone‐H3 variant, plays an essential role in cell division by ensuring proper formation and function of centromeres and kinetochores. Elevated CENP‐A expression has been associated with cancer development. This study aimed to establish whether elevated CENP‐A expression can be used as a prognostic and predictive cancer biomarker. Molecular profiling of CENP‐A in human cancers was investigated using genomic, transcriptomic and patient information from databases, including COSMIC, Oncomine, Kaplan–Meier plotter and cBioPortal. A network of CENP‐A co‐expressed genes was derived from cBioPortal and analyzed using Ingenuity Pathway Analysis (IPA) and Oncomine protocols to explore the function of CENP‐A and its predictive potential. Transcriptional and post‐transcriptional regulation of CENP‐A expression was analyzed in silico. It was found that CENP‐A expression was elevated in 20 types of solid cancer compared with normal counterparts. Elevated CENP‐A expression highly correlated with cancer progression and poor patient outcome. Genomic analysis indicated that the elevated CENP‐A expression was not due to alterations in the sequence or copy number of the CENP‐A gene. Furthermore, CENP‐A can be regulated by key oncogenic proteins and tumor‐suppressive microRNAs. CENP‐A co‐expression network analysis indicated that CENP‐A function is associated with cell cycle progression. Oncomine analysis showed a strong correlation between elevated CENP‐A expression and oncolytic response of breast cancer patients to taxane‐based chemotherapy. In conclusion, elevated CENP‐A expression is coupled to malignant progression of numerous types of cancer. It may be useful as a biomarker of poor patient prognosis and as a predictive biomarker for taxane‐based chemotherapy.

BackgroundWhile localized prostate cancer (PCa) can be effectively cured, metastatic disease inevitably progresses to a lethal state called castration-resistant prostate cancer (CRPC). Emerging evidence suggests that aberrant epigenetic repression by the polycomb group (PcG) complexes fuels PCa progression, providing novel therapeutic opportunities.ResultsIn the search for potential epigenetic drivers of CRPC, we analyzed the molecular profile of PcG members in patient-derived xenografts and clinical samples. Overall, our results identify the PcG protein and methyl-lysine reader CBX2 as a potential therapeutic target in advanced PCa. We report that CBX2 was recurrently up-regulated in metastatic CRPC and that elevated CBX2 expression was correlated with poor clinical outcome in PCa cohorts. Furthermore, CBX2 depletion abrogated cell viability and induced caspase 3-mediated apoptosis in metastatic PCa cell lines. Mechanistically explaining this phenotype, microarray analysis in CBX2-depleted cells revealed that CBX2 controls the expression of many key regulators of cell proliferation and metastasis.ConclusionsTaken together, this study provides the first evidence that CBX2 inhibition induces cancer cell death, positioning CBX2 as an attractive drug target in lethal CRPC.