Going beyond Polycomb: EZH2 functions in prostate cancer.
Going beyond Polycomb: EZH2 functions in prostate cancer.
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超越Polycomb：EZH2在前列腺癌中的作用
DOI：
10.1038/s41388-021-01982-4
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发表时间：
2021-09
期刊：
影响因子：
8
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Park SH;Fong KW;Mong E;Martin MC;Schiltz GE;Yu J
Polycomb group（PcG）蛋白增强子Zeste同源物2（EZH 2）是Polycomb抑制复合物2（PRC 2）的三个核心亚基之一。它具有组蛋白甲基转移酶活性（MTase），特异性催化靶基因启动子上的组蛋白3赖氨酸27（H3 K27）甲基化。因此，PRC 2是表观遗传沉默子，在细胞身份和胚胎干细胞维持中发挥重要作用。在过去的二十年中，越来越多的证据支持EZH 2突变和/或过表达在广泛的血液癌症和实体瘤，包括前列腺癌。此外，EZH 2是神经内分泌前列腺癌中上调最多的基因之一，其由于高亲和力雄激素受体途径抑制剂的临床使用而变得丰富。虽然许多研究已经报道了EZH 2抑制肿瘤抑制基因和促进肿瘤发生的表观遗传功能，但已经报道了EZH 2和H3 K27甲基化之间的不一致性。此外，酶促EZH 2抑制剂在前列腺癌中显示出有限的功效，从而阻碍了对EZH 2功能的更全面理解。在这里，我们首先回顾了EZH 2作为组蛋白MTase的典型功能是如何调节的，并描述了PRC 2招募到染色质的各种机制。我们进一步概述了EZH 2的非组蛋白底物，并讨论了可能影响底物偏好的EZH 2本身的翻译后修饰。最后，我们总结了EZH 2的非经典功能，除了其MTase活性和/或PRC 2，作为转录辅因子，并讨论其在前列腺癌中的治疗靶向的前景。
The Polycomb group (PcG) protein Enhancer of Zeste Homolog 2 (EZH2) is one of the three core subunits of the Polycomb Repressive Complex 2 (PRC2). It harbors histone methyltransferase activity (MTase) that specifically catalyze histone 3 lysine 27 (H3K27) methylation on target gene promoters. As such, PRC2 are epigenetic silencers that play important roles in cellular identity and embryonic stem cell maintenance. In the past two decades, mounting evidence supports EZH2 mutations and/or over-expression in a wide array of hematological cancers and solid tumors, including prostate cancer. Further, EZH2 is among the most up-regulated genes in neuroendocrine prostate cancers, which become abundant due to the clinical use of high-affinity androgen receptor pathway inhibitors. While numerous studies have reported epigenetic functions of EZH2 that inhibit tumor suppressor genes and promote tumorigenesis, discordance between EZH2 and H3K27 methylation has been reported. Further, enzymatic EZH2 inhibitors have shown limited efficacy in prostate cancer, warranting a more comprehensive understanding of EZH2 functions. Here we first review how canonical functions of EZH2 as a histone MTase are regulated and describe the various mechanisms of PRC2 recruitment to the chromatin. We further outline non-histone substrates of EZH2 and discuss post-translational modifications to EZH2 itself that may affect substrate preference. Lastly, we summarize non-canonical functions of EZH2, beyond its MTase activity and/or PRC2, as a transcriptional cofactor and discuss prospects of its therapeutic targeting in prostate cancer.
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