Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
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DOI：
10.1158/0008-5472.can-18-2297
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发表时间：
2019-02-15
期刊：
影响因子：
11.2
通讯作者：
Drapkin, Ronny
中科院分区：
文献类型：
--
作者：
Hooda, Jagmohan;Novak, Marian;Drapkin, Ronny
最近的研究结果支持输卵管上皮（FTE）和浆液性输卵管上皮内癌（STIC）分别作为大多数高级别浆液性卵巢癌（HGSOC）的起源组织和前体病变，为研究驱动HGSOC发展和进展的机制提供了必要的背景。在这里，我们研究了E3泛素连接酶RNF20和组蛋白H2B单泛素化（H2Bub1）在浆液性肿瘤发生中的作用，并报道RNF20的杂合缺失定义了大多数HGSOC肿瘤。在蛋白水平上，在很大比例的STIC和侵袭性HGSOC肿瘤中，H2Bub1缺失或下调，这意味着RNF20/H2Bub1缺失是浆液性卵巢癌发展的早期事件。RNF20的敲低，伴随H2Bub1的缺失，足以增强FTE细胞的细胞迁移和克隆生长。为了研究这些影响的机制，我们对RNF20基因敲除的FTE细胞系进行了ATAC-seq和RNA-seq。RNF20和H2Bub1的缺失与更开放的染色质构象相关，导致免疫信号通路上调，包括IL6。IL6是RNF20-和h2bub1缺失的FTE细胞中显著上调的关键细胞因子之一，并赋予这些细胞增强的迁移表型。这些研究为观察到的由H2Bub1早期缺失引发的致癌表型提供了机制见解。意义：RNF20和H2Bub1的缺失有助于输卵管上皮的转化，并在高级别浆液性卵巢癌的发生和发展中发挥作用。图形摘要：http://cancerres.aacrjournals.org/content/canres/79/4/760/F1.large.jpg。
Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1.Significance: Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/4/760/F1.large.jpg.