Zhao Hongying, Liu Xiaoqin, Yu Lei, Lin Shihua, Zhang Caiyu, Xu Haotian, Leng Zhijun, Huang Waidong, Lei Junjie, Li Tengyue, Li Jing, Yang Fan, Wang Li
College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China.
School of Life Sciences, Westlake University, Hangzhou 310024, China.
Mol Ther Nucleic Acids. 2021 Jan 1;23:667-681. doi: 10.1016/j.omtn.2020.12.024. eCollection 2021 Mar 5.
Aberrant expression of long non-coding RNAs (lncRNA) is associated with altered DNA methylation and histone modifications during carcinogenesis. However, identifying epigenetically dysregulated lncRNAs and characterizing their functional mechanisms in different cancer subtypes are still major challenges for cancer studies. In this study, we systematically analyzed the epigenetic alterations of lncRNAs at important regulatory elements in three breast cancer subtypes. We identified 87, 691, and 1,197 epigenetically dysregulated lncRNAs in luminal, basal, and claudin-low subtypes of breast cancer, respectively. The landscape of epigenetically dysregulated lncRNAs at enhancer elements revealed that epigenetic changes of the majority of lncRNAs occurred in a subtype-specific manner and contributed to subtype-specific biological functions. We identified six acetylation of lysine 27 on histone H3 (H3K27ac)-dysregulated lncRNAs and three DNA methylation-dysregulated lncRNAs (CTC-303L1.2, RP11-738B7.1, and SLC26A4-AS1) as prognostic biomarkers of basal subtype. These lncRNAs were involved in immune response-related biological functions. Treatment of the basal breast cancer cell line MDA-MB-468 with CREBBP/EP300 bromodomain inhibitors downregulated H3K27 acetylation levels and caused a decrease in the expression of five H3K27ac-dysregulated lncRNAs (LINC00393, KB-1836B5.1, RP1-140K8.5, AC005162.1, and AC020916.2) and inhibition of the growth of breast cancer cells. One epigenetically dysregulated lncRNA (LINC01983) and four lncRNA regulators (UCA1, RP11-221J22.2, RP11-221J22.1, and RP1-212P9.3) were identified as prognostic biomarkers of the luminal molecular subtype of breast cancer by controlling the tumor necrosis factor (TNF) signaling pathway, T helper (Th)17 cell differentiation, and T cell migration. Finally, our results highlighted a profound role of enhancer-related H3K27ac-dysregulated lncRNAs, DNA methylation-dysregulated lncRNAs, and lncRNA regulators in breast cancer subtype carcinogenesis and their potential prognostic value.
长链非编码RNA（lncRNA）的异常表达与癌症发生过程中DNA甲基化和组蛋白修饰的改变有关。然而，识别表观遗传失调的lncRNAs并阐明它们在不同癌症亚型中的功能机制仍然是癌症研究的主要挑战。在本研究中，我们系统地分析了三种乳腺癌亚型重要调控元件处lncRNAs的表观遗传改变。我们分别在乳腺癌的管腔型、基底型和Claudin-low亚型中鉴定出87个、691个和1,197个表观遗传失调的lncRNAs。增强子元件处表观遗传失调lncRNAs的图谱显示，大多数lncRNAs的表观遗传变化以亚型特异性方式发生，并促成了亚型特异性生物学功能。我们鉴定出6个组蛋白H3赖氨酸27乙酰化（H3K27ac）失调的lncRNAs和3个DNA甲基化失调的lncRNAs（CTC-303L1.2、RP11-738B7.1和SLC26A4-AS1）作为基底型亚型的预后生物标志物。这些lncRNAs参与免疫反应相关的生物学功能。用CREBBP/EP300溴结构域抑制剂处理基底型乳腺癌细胞系MDA-MB-468可下调H3K27乙酰化水平，并导致5个H3K27ac失调lncRNAs（LINC00393、KB-1836B5.1、RP1-140K8.5、AC005162.1和AC020916.2）的表达降低，并抑制乳腺癌细胞生长。通过控制肿瘤坏死因子（TNF）信号通路、辅助性T细胞（Th）17细胞分化和T细胞迁移，鉴定出1个表观遗传失调的lncRNA（LINC01983）和4个lncRNA调控因子（UCA1、RP11-221J22.2、RP11-221J22.1和RP1-212P9.3）作为乳腺癌管腔分子亚型的预后生物标志物。最后，我们的结果突出了增强子相关的H3K27ac失调lncRNAs、DNA甲基化失调lncRNAs和lncRNA调控因子在乳腺癌亚型致癌过程中的重要作用及其潜在的预后价值。
