The RING finger domain E3 ubiquitin ligases BRCA1 and the RNF20/RNF40 complex in global loss of the chromatin mark histone H2B monoubiquitination (H2Bub1) in cell line models and primary high-grade serous ovarian cancer
The RING finger domain E3 ubiquitin ligases BRCA1 and the RNF20/RNF40 complex in global loss of the chromatin mark histone H2B monoubiquitination (H2Bub1) in cell line models and primary high-grade serous ovarian cancer
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DOI：
10.1093/hmg/ddw362
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发表时间：
2016-12-15
影响因子：
3.5
通讯作者：
Marsh, Deborah J.
中科院分区：
文献类型：
--
作者：
Dickson, Kristie-Ann;Cole, Alexander J.;Marsh, Deborah J.
随着癌症表观基因组在基因表达和DNA修复过程中的作用的阐明，驱动癌症相关染色质重塑的酶促因素越来越受到关注。组蛋白H2 B在赖氨酸120（H2 Bub 1）处的单泛素化（Monoubiquitination）是一种中心组蛋白修饰，其在组蛋白串扰、转录延伸、DNA修复、维持着丝粒染色质和复制依赖性组蛋白mRNA 3 '端加工中起作用，并且是干细胞分化所需的。在许多侵袭性恶性肿瘤中可以看到全局H2 Bub 1的丢失，并且与某些癌症的肿瘤进展和/或预后较差有关。在这里，我们分析了一个大的高级别浆液性卵巢癌（HGSOC）队列，并显示77%（407例中的313例）的肿瘤中H2 Bub 1的整体丢失。在HGSOC的所有阶段（I-IV）均观察到H2 Bub 1的缺失，表明其是这种侵袭性恶性肿瘤中相对早期的表观基因组事件。在卵巢癌细胞系模型中操纵关键的H2 Bub 1 E3泛素连接酶RNF 20、RNF 40和BRCA 1调节H2 Bub 1水平，表明这些RING指连接酶在体外H2 Bub 1单泛素化中的作用。然而，在原发性HGSOC中，仅6%的肿瘤（424例中的26例）发现RNF 20蛋白表达缺失，并且与整体H2 Bub 1缺失无关。同样，BRCA 1的生殖系突变也没有显示出与整体H2 Bub 1丢失的相关性。我们的结论是，肿瘤相关的H2 Bub 1水平的调节是复杂的。异常表达的替代组蛋白相关的“作家”或“擦除”酶可能是负责全球损失H2 Bub 1看到HGSOC。
Enzymatic factors driving cancer-associated chromatin remodelling are of increasing interest as the role of the cancer epigenome in gene expression and DNA repair processes becomes elucidated. Monoubiquitination of histone H2B at lysine 120 (H2Bub1) is a central histone modification that functions in histone cross-talk, transcriptional elongation, DNA repair, maintaining centromeric chromatin and replication-dependent histone mRNA 3'-end processing, as well as being required for the differentiation of stem cells. The loss of global H2Bub1 is seen in a number of aggressive malignancies and has been linked to tumour progression and/or a poorer prognosis in some cancers. Here, we analyse a large cohort of high-grade serous ovarian cancers (HGSOC) and show loss of global H2Bub1 in 77% (313 of 407) of tumours. Loss of H2Bub1 was seen at all stages (I-IV) of HGSOC, indicating it is a relatively early epigenomic event in this aggressive malignancy. Manipulation of key H2Bub1 E3 ubiquitin ligases, RNF20, RNF40 and BRCA1, in ovarian cancer cell line models modulated H2Bub1 levels, indicative of the role of these RING finger ligases in monoubiquitination of H2Bub1 in vitro. However, in primary HGSOC, loss of RNF20 protein expression was identified in just 6% of tumours (26 of 424) and did not correlate with global H2Bub1 loss. Similarly, germline mutation of BRCA1 did not show a correlation with the global H2Bub1 loss. We conclude that the regulation of tumour-associated H2Bub1 levels is complex. Aberrant expression of alternative histone-associated 'writer' or 'eraser' enzymes are likely responsible for the global loss of H2Bub1 seen in HGSOC.