Polycomb-mediated silencing in neuroendocrine prostate cancer.
Polycomb-mediated silencing in neuroendocrine prostate cancer.
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DOI：
10.1186/s13148-015-0074-4
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发表时间：
2015
影响因子：
5.7
通讯作者：
Helgason CD
中科院分区：
文献类型：
--
作者：
Clermont PL;Lin D;Crea F;Wu R;Xue H;Wang Y;Thu KL;Lam WL;Collins CC;Wang Y;Helgason CD
神经内分泌前列腺癌（NEPC）是前列腺癌（PCa）的一种高度侵袭性亚型，其中位生存期不到一年。目前的治疗方法本质上只是姑息性的，缺乏合适的临床前模型阻碍了以前开发新的治疗策略的努力。为了满足这一需求，我们最近建立了第一个使用患者来源的异种移植物进行完全神经内分泌转分化的体内模型。在父母PCa和复发NEPC之间观察到很少的遗传差异，这表明NEPC可能是由表观遗传性质的改变引起的。因此，我们试图使用患者来源的异种移植物和临床样品的全基因组分析来鉴定其表达在NEPC中升高的靶向表观遗传调节剂。我们的数据表明，多梳组（PcG）家族的转录抑制因子的多个成员选择性上调NEPC。值得注意的是，CBX 2和EZH 2在来自临床和异种移植肿瘤组织的多个数据集中始终是最高度过表达的表观遗传调节因子。考虑到PcG基因和其他转录抑制因子的显著上调，我们通过重叠在多个体内NEPC模型中下调的转录物，推导出了一个称为“神经内分泌相关抑制信号”（NEARS）的185个基因列表。与PcG家族成员的显著上调一致，NEARS优先富集PcG靶基因，表明PcG沉默在NEPC中的驱动作用。重要的是，在多个临床数据集中，NEARS与高级别肿瘤、转移性进展和不良结局显著相关，这与PcG基因和侵袭性疾病进展相关的大量文献一致。我们已经探索了NEPC的表观遗传学景观，并提供了增加的PcG介导的沉默与关键分化基因的异常转录调控相关的证据。我们的研究结果将CBX 2和EZH 2定位为NEPC的潜在治疗靶点，为探索旨在逆转驱动这种致命疾病的表观遗传学改变的新策略提供了机会。本文的在线版本（doi：10.1186/s13148-015-0074-4）包含补充材料，可供授权用户使用。
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. 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. 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. The 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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影响因子：
8.8
作者：
Clermont, P-L;Sun, L.;Crea, F.;Thu, K. L.;Zhang, A.;Parolia, A.;Lam, W. L.;Helgason, C. D.
通讯作者：
Helgason, C. D.
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
Katoh-Fukui, Y;Tsuchiya, R;Higashinakagawa, T
通讯作者：
Higashinakagawa, T
影响因子：
10.5
作者：
Berger, Shelley L.;Kouzarides, Tony;Shilatifard, Ali
通讯作者：
Shilatifard, Ali
影响因子：
64.5
作者：
Goldberg, Aaron D.;Allis, C. David;Bernstein, Emily
通讯作者：
Bernstein, Emily