Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner.
Epigenetic Therapies in Ovarian Cancer Alter Repetitive Element Expression in a TP53-Dependent Manner.
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DOI：
10.1158/0008-5472.can-20-4243
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Chiappinelli KB
中科院分区：
文献类型：
--
作者：
McDonald JI;Diab N;Arthofer E;Hadley M;Kanholm T;Rentia U;Gomez S;Yu A;Grundy EE;Cox O;Topper MJ;Xing X;Strissel PL;Strick R;Wang T;Baylin SB;Chiappinelli KB
上皮性卵巢癌（OC）由于肿瘤内异质性，对标准治疗的耐药性以及对替代治疗（如免疫治疗）的反应差而特别致命。用DNA甲基转移酶抑制剂（DNMTi）或组蛋白脱乙酰酶抑制剂（HDACi）靶向OC表观基因组可增加免疫信号传导，并招募CD 8 + T细胞和NK细胞来对抗小鼠模型中的OC。这种增加的免疫活性是由形成双链RNA（dsRNA）并触发干扰素应答的重复元件（RE）的转录增加引起的。为了了解OC中哪些RE受到表观遗传疗法的影响，我们评估了DNMTi和HDACi对OC细胞系和患者样品的影响。RE的亚家族水平（TE转录物）和个体基因座水平（Telescope）分析表明，DNMTi处理比HDACi处理上调更多的RE。上调的RE主要是LTR和SINE亚家族，并且西内斯在DNMTi处理后表现出最大的DNA甲基化损失。与野生型TP 53细胞系相比，具有TP 53突变的细胞系在表观遗传疗法下表现出显著更少的上调RE。使用等基因细胞系验证了这一观察结果; TP 53突变细胞系具有显著更高的RE基线表达，但在表观遗传处理后上调较少。此外，p53激活增加了野生型而非突变型细胞系中RE的表达。这些数据提供了一个全面的，全基因组的图片RE染色质和转录相关的变化后，OC表观遗传治疗和牵连p53在RE转录调控。
Epithelial ovarian carcinomas (OC) are particularly deadly due to intratumoral heterogeneity, resistance to standard-of-care therapies, and poor response to alternative treatments such as immunotherapy. Targeting the OC epigenome with DNA methyltransferase inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi) increases immune signaling and recruits CD8+ T cells and NK cells to fight OC in murine models. This increased immune activity is caused by increased transcription of repetitive elements (RE) that form double-stranded RNA (dsRNA) and trigger an interferon response. To understand which REs are affected by epigenetic therapies in OC, we assessed the effect of DNMTi and HDACi on OC cell lines and patient samples. Subfamily-level (TEtranscripts) and individual locus-level (Telescope) analysis of REs showed that DNMTi treatment upregulated more REs than HDACi treatment. Upregulated REs were predominantly LTR and SINE subfamilies, and SINEs exhibited the greatest loss of DNA methylation upon DNMTi treatment. Cell lines with TP53 mutations exhibited significantly fewer upregulated REs with epigenetic therapy than wild type TP53 cell lines. This observation was validated using isogenic cell lines; the TP53 mutant cell line had significantly higher baseline expression of REs but upregulated fewer upon epigenetic treatment. In addition, p53 activation increased expression of REs in wild type but not mutant cell lines. These data give a comprehensive, genome-wide picture of RE chromatin and transcription-related changes in OC after epigenetic treatment and implicate p53 in RE transcriptional regulation.